bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2025–04–13
fifty-one papers selected by
Chun-Chi Chang, Universitäts Spital Zürich
  1. Skin Microbiome Dynamics in Atopic Dermatitis: Understanding Host-Microbiome Interactions.
  2. Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation.
  3. QDS pathoblockers target and lock α-hemolysin.
  4. Succinate contributes to Staphylococcus aureus skin infection by reactive oxygen species-hypoxic inducible factor 1α-glycolysis axis.
  5. Sex-dependent gastrointestinal colonization resistance to MRSA is microbiota and Th17 dependent.
  6. Advocating the role of trained immunity in the pathogenesis of ME/CFS: a mini review.
  7. Post-viral lung diseases: the microbiota as a key player.
  8. Psychological stress increases skin infection through the action of TGFβ to suppress immune-acting fibroblasts.
  9. Clinical translation of microbiome research.
  10. Modulation of pulmonary immune functions by the Pseudomonas aeruginosa secondary metabolite pyocyanin.
  11. Leveraging strain competition to address antimicrobial resistance with microbiota therapies.
  12. Generation of induced alveolar assembloids with functional alveolar-like macrophages.
  13. SLC27A2 marks lipid peroxidation in nasal epithelial cells driven by type 2 inflammation in chronic rhinosinusitis with nasal polyps.
  14. Neutrophils make matrix to fortify barrier immunity.
  15. Unraveling the role of HIF-1α in allergic rhinitis: A key regulator of epithelial barrier integrity via PI3K pathway.
  16. Asparagine transporter supports macrophage inflammation via histone phosphorylation.
  17. Oxidative stress and central metabolism pathways impact epigenetic modulation in inflammation and immune response.
  18. Genetic and immunological regulation of gut Microbiota: The Roles of TLRs, CLRs, and key proteins in microbial homeostasis and disease.
  19. Mechanisms of ferroptosis sensitization and resistance.
  20. Gut bacterial lactate stimulates lung epithelial mitochondria and exacerbates acute lung injury.
  21. Mobile genetic elements: the hidden puppet masters underlying infant gut microbiome assembly?
  22. Mitochondrial dynamics at the intersection of macrophage polarization and metabolism.
  23. Pathogen-targeting biomineralized bacterial outer membrane vesicles for eradicating both intracellular and extracellular Staphylococcus aureus.
  24. When glycobiology meets inflammasome activation: Insights and implications.
  25. Macrophage Polarization in Lung Diseases: From Mechanisms to Therapeutic Strategies.
  26. TFEB and TFE3 regulate STING1-dependent immune responses by controlling type I interferon signaling.
  27. Dynamic regulation of neutrophil immunometabolism by platelet-derived metabolites.
  28. Host AAA-ATPase VCP/p97 lyses ubiquitinated intracellular bacteria as an innate antimicrobial defence.
  29. Immune responses in the skin: Not so skinny at all.
  30. The metabolites of gut microbiota: their role in ferroptosis in inflammatory bowel disease.
  31. Innate immune signals triggered on organelle membranes.
  32. Early secretory antigen target of 6-kDa of Mycobacterium tuberculosis inhibits macrophage apoptosis and host defense via TLR2.
  33. Cellular stress and macrophage activation.
  34. Metabolic state-driven nutrient-based approach to combat bacterial antibiotic resistance.
  35. CFTR function in alveolar type 1 cells drives lung liquid secretion and host defense.
  36. M2 macrophage-derived exosomes reverse TGF-β1-induced epithelial mesenchymal transformation in BEAS-2B cells via the TGF-βRI/Smad2/3 signaling pathway.
  37. Mucosal stargazing: IgA keeps astrovirus in check.
  38. The PERK-ATF4 pathway is required for metabolic reprogramming and progressive lung fibrosis.
  39. Identification of the Pseudomonas aeruginosa AgtR-CspC-RsaL pathway that controls Las quorum sensing in response to metabolic perturbation and Staphylococcus aureus.
  40. Plant-made trained immunity-based vaccines: Beyond one approach.
  41. The impact of environmental factors on respiratory tract microbiome and respiratory system diseases.
  42. Trained immunity alleviates the progression of melanoma during sepsis-associated immunoparalysis.
  43. Protocol for microbial profiling of low-biomass upper respiratory tract samples.
  44. Staphylococcus aureus β-hemolysin impairs oxygen transport without causing hemolysis.
  45. Heritable maintenance of chromatin modifications confers transcriptional memory of interferon-γ signaling.
  46. Glycan-mediated adhesion mechanisms in antibiotic-resistant bacteria.
  47. Roles of Circadian Clocks in Macrophage Metabolism: Implications in Inflammation, and Metabolism of Lipids, Glucose, and Amino Acids.
  48. Exploring the antimicrobial potential of lactobacilli against early-stage and mature biofilms of Staphylococcus aureus and Pseudomonas aeruginosa.
  49. Polychlorinated biphenyls induce immunometabolic switch of antiinflammatory macrophages toward an inflammatory phenotype.
  50. Reprogram to heal: Macrophage phenotypes as living therapeutics.
  51. TLR4 endocytosis and endosomal TLR4 signaling are distinct and independent outcomes of TLR4 activation.
  1. Allergy Asthma Immunol Res. 2025 Mar;17(2): 165-180
    Skin Microbiome Dynamics in Atopic Dermatitis: Understanding Host-Microbiome Interactions.
    Han Bi Kim, Helen Alexander, Ji Young Um, Bo Young Chung, Chun Wook Park, Carsten Flohr, Hye One Kim.
      Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting both children and adults, characterized by pruritus, eczematous lesions, and compromised skin barrier function. A key feature of AD is dysbiosis of the skin microbiome, marked by reduced microbial diversity and the overgrowth of Staphylococcus aureus in lesional skin. S. aureus exacerbates skin barrier dysfunction and immune dysregulation, leading to recurrent infections and disease flares. In contrast, commensal bacteria such as Staphylococcus epidermidis and Roseomonas mucosa may exert protective effects by inhibiting S. aureus colonization and modulating immune responses. Beyond microbial composition, microbial metabolites play a crucial role in AD pathophysiology. Short-chain fatty acids, indole derivatives, and other bacterial metabolites influence cutaneous immune responses, lipid metabolism, and skin barrier integrity. Altered metabolite profiles, including reduced levels of beneficial microbial metabolites, are associated with AD severity and disease progression. Notably, S. aureus overabundance correlates with disruption in lipid metabolism, further compromising the skin barrier. This review explores recent advances in understanding the relationship between microbial metabolites and AD pathogenesis and examines the therapeutic potential of microbiome-targeted interventions. Strategies such as probiotics, prebiotics, and topical microbiome transplantation aim to restore microbial diversity and rebalance metabolite production, ultimately improving clinical outcomes in AD patients. Future therapeutic approaches focusing on commensal-derived metabolites offer promising avenues for alleviating symptoms and modulating disease severity in AD.
    Keywords:  Atopic dermatitis; metabolites; microbiome
    DOI:  https://doi.org/10.4168/aair.2025.17.2.165
  2. Nat Commun. 2025 Apr 04. 16(1): 3230
    Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation.
    Huanhuan Cai, Xueyuan Chen, Yan Liu, Yingbo Chen, Gechang Zhong, Xiaoyu Chen, Shuo Rong, Hao Zeng, Lin Zhang, Zelong Li, Aihua Liao, Xiangtai Zeng, Wei Xiong, Cihang Guo, Yanfang Zhu, Ke-Qiong Deng, Hong Ren, Huan Yan, Zeng Cai, Ke Xu, Li Zhou, Zhibing Lu, Fubing Wang, Shi Liu.
      Trained immunity refers to the long-term memory of the innate immune cells. However, little is known about how environmental nutrient availability influences trained immunity. This study finds that physiologic carbon sources impact glucose contribution to the tricarboxylic acid (TCA) cycle and enhance cytokine production of trained monocytes. Our experiments demonstrate that trained monocytes preferentially employe lactate over glucose as a TCA cycle substrate, and lactate metabolism is required for trained immune cell responses to bacterial and fungal infection. Except for the contribution to the TCA cycle, endogenous lactate or exogenous lactate also supports trained immunity by regulating histone lactylation. Further transcriptome analysis, ATAC-seq, and CUT&Tag-seq demonstrate that lactate enhance chromatin accessibility in a manner dependent histone lactylation. Inhibiting lactate-dependent metabolism by silencing lactate dehydrogenase A (LDHA) impairs both lactate fueled the TCA cycle and histone lactylation. These findings suggest that lactate is the hub of immunometabolic and epigenetic programs in trained immunity.
    DOI:  https://doi.org/10.1038/s41467-025-58563-2
  3. Cell Host Microbe. 2025 Apr 09. pii: S1931-3128(25)00085-X. [Epub ahead of print]33(4): 464-466
    QDS pathoblockers target and lock α-hemolysin.
    Yanan Wang, Min Li.
      Staphylococcus aureus is a major pathogen with rising antibiotic resistance. In this issue of Cell Host & Microbe, Shekhar et al. find that quinoxalinediones reduce S. aureus lung infections through α-hemolysin inhibition, offering a therapeutic strategy for S. aureus pneumonia.
    DOI:  https://doi.org/10.1016/j.chom.2025.03.002
  4. Microb Pathog. 2025 Apr 02. pii: S0882-4010(25)00254-2. [Epub ahead of print]204 107529
    Succinate contributes to Staphylococcus aureus skin infection by reactive oxygen species-hypoxic inducible factor 1α-glycolysis axis.
    Xing Gao, Min Yu, Tianfeng Huang, Yali Ge, Ju Gao.
      Skin and soft tissue infections (SSTIs) caused by Staphylococcus aureus (S. aureus), one of the most prevalent and refractory diseases in humans and animals, are potentially involved in the metabolic reprogramming of pathogens and hosts. This study identified succinate as a danger signal. Succinate elevates mitochondrial ROS (mROS) levels, leading to higher HIF1α expression and glycolysis. These changes ultimately drive inflammation. Moreover, as a metabolite shared by pathogens and hosts, succinate facilitated metabolic crosstalk during infection. Through the deletion of S. aureus sucD, our results demonstrated that succinate derived from S. aureus exacerbated infection-induced inflammation. Additionally, our observations revealed consistently high expression levels of S. aureus fumC, a downstream enzyme in succinate metabolism, during skin infection, which maintained elevated glycolysis levels through the depletion of fumarate in the infectious environment. Overall, our findings elucidated the mechanism by which succinate regulates glycolysis via the mROS-HIF1α axis and provided support for targeting bacterial metabolism as a mechanism to prevent bacterial metabolic reprogramming and the development of skin infection.
    Keywords:  Glycolysis; Skin infection; Staphylococcus aureus; Succinate; mROS-HIF1α
    DOI:  https://doi.org/10.1016/j.micpath.2025.107529
  5. Elife. 2025 Apr 08. pii: RP101606. [Epub ahead of print]13
    Sex-dependent gastrointestinal colonization resistance to MRSA is microbiota and Th17 dependent.
    Alannah Lejeune, Chunyi Zhou, Defne Ercelen, Gregory Putzel, Xiaomin Yao, Alyson R Guy, Miranda Pawline, Magdalena Podkowik, Alejandro Pironti, Victor J Torres, Bo Shopsin, Ken Cadwell.
      Gastrointestinal (GI) colonization by methicillin-resistant Staphylococcus aureus (MRSA) is associated with a high risk of transmission and invasive disease in vulnerable populations. The immune and microbial factors that permit GI colonization remain unknown. Male sex is correlated with enhanced Staphylococcus aureus nasal carriage, skin and soft tissue infections, and bacterial sepsis. Here, we established a mouse model of sexual dimorphism during GI colonization by MRSA. Our results show that in contrast to male mice that were susceptible to persistent colonization, female mice rapidly cleared MRSA from the GI tract following oral inoculation in a manner dependent on the gut microbiota. This colonization resistance displayed by female mice was mediated by an increase in IL-17A+ CD4+ T cells (Th17) and dependent on neutrophils. Ovariectomy of female mice increased MRSA burden, but gonadal female mice that have the Y chromosome retained enhanced Th17 responses and colonization resistance. Our study reveals a novel intersection between sex and gut microbiota underlying colonization resistance against a major widespread pathogen.
    Keywords:  GI tract; MRSA; Th17; colonization resistance; immunology; inflammation; microbiota; mouse; sex hormone
    DOI:  https://doi.org/10.7554/eLife.101606
  6. Front Immunol. 2025 ;16 1483764
    Advocating the role of trained immunity in the pathogenesis of ME/CFS: a mini review.
    Bart Humer, Willem A Dik, Marjan A Versnel.
      Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic disease of which the underlying (molecular) mechanisms are mostly unknown. An estimated 0.89% of the global population is affected by ME/CFS. Most patients experience a multitude of symptoms that severely affect their lives. These symptoms include post-exertional malaise, chronic fatigue, sleep disorder, impaired cognitive functions, flu-like symptoms, and chronic immune activation. Therapy focusses on symptom management, as there are no drugs available. Approximately 60% of patients develop ME/CFS following an acute infection. Such a preceding infection may induce a state of trained immunity; defined as acquired, nonspecific, immunological memory of innate immune cells. Trained immune cells undergo long term epigenetic reprogramming, which leads to changes in chromatin accessibility, metabolism, and results in a hyperresponsive phenotype. Initially, trained immunity has only been demonstrated in peripheral blood monocytes and macrophages. However, more recent findings indicate that hematopoietic stem cells in the bone marrow are required for long-term persistence of trained immunity. While trained immunity is beneficial to combat infections, a disproportionate response may cause disease. We hypothesize that pronounced hyperresponsiveness of innate immune cells to stimuli could account for the aberrant activation of various immune pathways, thereby contributing to the pathophysiology of ME/CFS. In this mini review, we elaborate on the concept of trained immunity as a factor involved in the pathogenesis of ME/CFS by presenting evidence from other post-infectious diseases with symptoms that closely resemble those of ME/CFS.
    Keywords:  ME/CFS; PASC; epigenetics; innate immunity; metabolomics; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2025.1483764
  7. ERJ Open Res. 2025 Mar;pii: 00560-2024. [Epub ahead of print]11(2):
    Post-viral lung diseases: the microbiota as a key player.
    Sabine V Stadler, Christophe von Garnier, Niki D Ubags.
      Viral infections of the respiratory tract can lead to chronic lung injury through immunopathological mechanisms that remain unclear. Communities of commensal bacteria colonising the respiratory tract, known as the respiratory tract microbiota, are altered in viral infections, which can contribute to inflammation, lung epithelial damage and subsequent development of lung disease. Emerging evidence on post-viral lung injury suggests an interplay between viral infections, immune responses and airway microbiota composition in the development of viral-induced lung diseases. In this review, we present the clinical characteristics of post-viral lung injury, along with the underlying immunopathological mechanisms and host-bacteria interactions, with a focus on influenza virus, respiratory syncytial virus and coronaviruses. Additionally, considering the important role of the airway microbiota in viral-induced pulmonary sequelae, we suggest key areas for future research on respiratory microbiota involvement in the development of post-viral lung diseases.
    DOI:  https://doi.org/10.1183/23120541.00560-2024
  8. Sci Immunol. 2025 Apr 11. 10(106): eads0519
    Psychological stress increases skin infection through the action of TGFβ to suppress immune-acting fibroblasts.
    Hung Chan, Fengwu Li, Tatsuya Dokoshi, Kellen J Cavagnero, Qing Li, Yang Chen, Carlos Aguilera, Teruaki Nakatsuji, Edward Liu, Aaryan Indra, Daping Yang, Ottaviani Valentina, Tomofumi Numata, Brittany Crown, Henry Li, Kevin J Williams, Isaac M Chiu, Steven J Bensinger, WanJun Chen, Richard L Gallo.
      Infections after psychological stress are a major health care problem. Single-cell transcriptomics and lipidomic profiling in a mouse model of stress show that dermal fibroblasts undergoing adipogenesis have defective responses to Staphylococcus aureus skin infection. Adrenalectomy or adrenergic inhibition restores the fibroblast adipogenic response to S. aureus and enables mice to effectively resist infection during stress. Increased susceptibility to S. aureus from stress is attributed to suppression of the antimicrobial peptide cathelicidin (Camp) because adrenaline directly inhibits Camp production by fibroblasts, and mice lacking Camp in fibroblasts do not increase infection after stress. Transforming growth factor β (TGFβ) is induced by stress and adrenergic signaling, and inhibition of TGFβ or deletion of the TGFβ receptor on fibroblasts increases Camp expression and restores protection against infection. Together, these data show that stress initiates a brain-skin axis mediated by TGFβ that impairs the immune defense function of dermal fibroblasts to produce the Camp antimicrobial peptide.
    DOI:  https://doi.org/10.1126/sciimmunol.ads0519
  9. Nat Med. 2025 Apr 11.
    Clinical translation of microbiome research.
    Jack A Gilbert, Meghan B Azad, Fredrik Bäckhed, Martin J Blaser, Mariana Byndloss, Charles Y Chiu, Hiutung Chu, Lara R Dugas, Eran Elinav, Sean M Gibbons, Katharine E Gilbert, Matthew R Henn, Suzanne L Ishaq, Ruth E Ley, Susan V Lynch, Eran Segal, Tim D Spector, Philip Strandwitz, Jotham Suez, Carolina Tropini, Katrine Whiteson, Rob Knight.
      The landscape of clinical microbiome research has dramatically evolved over the past decade. By leveraging in vivo and in vitro experimentation, multiomic approaches and computational biology, we have uncovered mechanisms of action and microbial metrics of association and identified effective ways to modify the microbiome in many diseases and treatment modalities. This Review explores recent advances in the clinical application of microbiome research over the past 5 years, while acknowledging existing barriers and highlighting opportunities. We focus on the translation of microbiome research into clinical practice, spearheaded by Food and Drug Administration (FDA)-approved microbiome therapies for recurrent Clostridioides difficile infections and the emerging fields of microbiome-based diagnostics and therapeutics. We highlight key examples of studies demonstrating how microbiome mechanisms, metrics and modifiers can advance clinical practice. We also discuss forward-looking perspectives on key challenges and opportunities toward integrating microbiome data into routine clinical practice, precision medicine and personalized healthcare and nutrition.
    DOI:  https://doi.org/10.1038/s41591-025-03615-9
  10. Front Immunol. 2025 ;16 1550724
    Modulation of pulmonary immune functions by the Pseudomonas aeruginosa secondary metabolite pyocyanin.
    Shi Qian Lew, Sook Yin Chong, Gee W Lau.
      Pseudomonas aeruginosa is a prevalent opportunistic Gram-negative bacterial pathogen. One of its key virulence factors is pyocyanin, a redox-active phenazine secondary metabolite that plays a crucial role in the establishment and persistence of chronic infections. This review provides a synopsis of the mechanisms through which pyocyanin exacerbates pulmonary infections. Pyocyanin induces oxidative stress by generating reactive oxygen and nitrogen species which disrupt essential defense mechanisms in respiratory epithelium. Pyocyanin increases airway barrier permeability and facilitates bacterial invasion. Pyocyanin also impairs mucociliary clearance by damaging ciliary function, resulting in mucus accumulation and airway obstruction. Furthermore, it modulates immune responses by promoting the production of pro-inflammatory cytokines, accelerating neutrophil apoptosis, and inducing excessive neutrophil extracellular trap formation, which exacerbates lung tissue damage. Additionally, pyocyanin disrupts macrophage phagocytic function, hindering the clearance of apoptotic cells and perpetuating inflammation. It also triggers mucus hypersecretion by inactivating the transcription factor FOXA2 and enhancing the IL-4/IL-13-STAT6 and EGFR-AKT/ERK1/2 signaling pathways, leading to goblet cell metaplasia and increased mucin production. Insights into the role of pyocyanin in P. aeruginosa infections may reveal potential therapeutic strategies to alleviate the severity of infections in chronic respiratory diseases including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).
    Keywords:  Pseudomonas aeruginosa; chronic lung diseases; immune modulation; oxidative stress; pyocyanin; reactive oxygen and nitrogen species
    DOI:  https://doi.org/10.3389/fimmu.2025.1550724
  11. Gut Microbes. 2025 Dec;17(1): 2488046
    Leveraging strain competition to address antimicrobial resistance with microbiota therapies.
    Danielle Barrios Steed, Dylan Koundakjian, Anthony D Harris, Adriana E Rosato, Konstantinos T Konstantinidis, Michael H Woodworth.
      The enteric microbiota is an established reservoir for multidrug-resistant organisms that present urgent clinical and public health threats. Observational data and small interventional studies suggest that microbiome interventions, such as fecal microbiota products and characterized live biotherapeutic bacterial strains, could be an effective antibiotic-sparing prevention approach to address these threats. However, bacterial colonization is a complex ecological phenomenon that remains understudied in the context of the human gut. Antibiotic resistance is one among many adaptative strategies that impact long-term colonization. Here we review and synthesize evidence of how bacterial competition and differential fitness in the context of the gut present opportunities to improve mechanistic understanding of colonization resistance, therapeutic development, patient care, and ultimately public health.
    Keywords:  Antibiotic resistance; bacterial competition; bacteriocins; fecal microbiota transplantation; microbiome; microbiota; quorum sensing
    DOI:  https://doi.org/10.1080/19490976.2025.2488046
  12. Nat Commun. 2025 Apr 09. 16(1): 3346
    Generation of induced alveolar assembloids with functional alveolar-like macrophages.
    Ji Su Kang, Youngsun Lee, Youngsun Lee, Dayeon Gil, Min Jung Kim, Connor Wood, Vincent Delorme, Jeong Mi Lee, Kyong-Cheol Ko, Jung-Hyun Kim, Mi-Ok Lee.
      Within the human lung, interactions between alveolar epithelial cells and resident macrophages shape lung development and function in both health and disease. To study these processes, we develop a co-culture system combining human pluripotent stem cell-derived alveolar epithelial organoids and induced macrophages to create a functional environment, termed induced alveolar assembloids. Using single-cell RNA sequencing and functional analyses, we identify alveolar type 2-like cells producing GM-CSF, which supports macrophage tissue adaptation, and macrophage-like cells that secrete interleukin-1β and interleukin-6, express surfactant metabolism genes, and demonstrate core immune functions. In response to alveolar epithelial injury, macrophage-like cells efficiently eliminate damaged cells and absorb oxidized lipids. Exposure to bacterial components or infection with Mycobacterium tuberculosis reveals that these assembloids replicate key aspects of human respiratory defense. These findings highlight the potential of induced alveolar assembloids as a platform to investigate human lung development, immunity, and disease.
    DOI:  https://doi.org/10.1038/s41467-025-58450-w
  13. Exp Mol Med. 2025 Apr 07.
    SLC27A2 marks lipid peroxidation in nasal epithelial cells driven by type 2 inflammation in chronic rhinosinusitis with nasal polyps.
    Jaewoo Park, Jung Yeon Jang, Jeong Heon Kim, Se Eun Yi, Yeong Ju Lee, Myeong Sang Yu, Yoo-Sam Chung, Yong Ju Jang, Ji Heui Kim, Kyuho Kang.
      Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by persistent inflammation and epithelial cell dysfunction, but the underlying molecular mechanisms remain poorly understood. Here we show that dysregulated lipid metabolism and increased lipid peroxidation in nasal polyp epithelial cells contribute to the pathogenesis of CRSwNP. Integrated analysis of bulk and single-cell RNA sequencing data reveals upregulation of SLC27A2/FATP2 in nasal polyp epithelium, which correlates with increased lipid peroxidation. SLC27A2-positive epithelial cells exhibit enriched expression of lipid peroxidation pathway genes and enhanced responsiveness to IL-4/IL-13 signaling from Th2 and ILC2 cells. Inhibition of IL-4/IL-13 signaling by dupilumab reduces expression of lipid peroxidation-associated genes, including SLC27A2. In eosinophilic CRSwNP, SLC27A2 expression correlates with disease severity. Pharmacological inhibition of FATP2 in air-liquid interface cultures of nasal epithelial cells decreases expression of IL13RA1 and lipid peroxidation-related genes. Our findings identify FATP2-mediated lipid peroxidation as a key driver of epithelial dysfunction and inflammation in CRSwNP, providing new insights into disease mechanisms and potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s12276-025-01440-1
  14. Nat Rev Immunol. 2025 Apr 09.
    Neutrophils make matrix to fortify barrier immunity.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-025-01170-5
  15. Tissue Cell. 2025 Mar 31. pii: S0040-8166(25)00178-8. [Epub ahead of print]95 102898
    Unraveling the role of HIF-1α in allergic rhinitis: A key regulator of epithelial barrier integrity via PI3K pathway.
    Zhuo Wu, Yongbo Zhang, Changzeng Zhou, Guxuan Zhang, Lei He, Ming Tang.
       BACKGROUND: Allergic rhinitis (AR) ranks among the most prevalent nasal disorders worldwide. Epithelial cells are the initial physiological barrier against allergen entry, and play a vital protective role. The precise role of hypoxia-inducible factor 1-alpha (HIF-1α) inhibitors in nasal epithelial cell injury in AR is still unknown, despite their confirmed association with nasal inflammation in AR models.
    METHODS: An interleukin-13 (IL-13)-induced AR cell model has been employed to investigate how HIF-1α inhibition impacts nasal epithelial cells (JME/CF15). Cell viability, inflammatory cytokines, mucosal remodeling factors, and the tight junction protein zonula occludens-1 (ZO-1) were evaluated using cell counting kit-8, enzyme-linked immunosorbent assay, Western blot, and immunofluorescence. The influences of phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways have been examined.
    RESULTS: PX-478 (a HIF-1α inhibitor) alleviated IL-13-induced epithelial barrier dysfunction by upregulating ZO-1 and reducing levels of inflammatory and remodeling factors. Mechanistically, HIF-1α activated the PI3K/MEK signaling pathway, exacerbating epithelial barrier disruption and inflammatory responses. Knockdown of HIF-1α suppressed PI3K pathway activation, mitigating inflammation and restoring barrier integrity. However, these protective effects were reversed by a PI3K agonist.
    CONCLUSIONS: HIF-1α aggravates AR by promoting inflammation, mucosal remodeling, and epithelial barrier dysfunction via PI3K pathway activation. This finding not only enriches our understanding of AR pathophysiology but also highlights HIF-1α and its downstream signaling pathways as prospective therapeutic targets for AR.
    Keywords:  Allergic rhinitis; Epithelial barrier dysfunction; Hypoxia-inducible factor-1α; Mucosal remodeling; Phosphoinositide 3-kinase pathway
    DOI:  https://doi.org/10.1016/j.tice.2025.102898
  16. Sci Adv. 2025 Apr 11. 11(15): eads3506
    Asparagine transporter supports macrophage inflammation via histone phosphorylation.
    Chuanlong Wang, Yuyi Ye, Muyang Zhao, Qingyi Chen, Bingnan Liu, Wenkai Ren.
      Solute carrier (SLC) family is essential for immune responses; nevertheless, whether and how SLCs regulate macrophage inflammation remains unclear. Here, we demonstrate that K636 acetylation mediates high abundance of SLC6A14 in inflammatory macrophages. Notably, the pharmacological inhibition or genetic modulation of SLC6A14 reduces macrophage interleukin-1β (IL-1β) secretion dependently of lower asparagine uptake and subsequently enhanced nuclear LKB1. Mechanistically, nuclear LKB1 lessens MAPK pathway-mediated NLRP3 inflammasome activation by increased histone 3 S10/28 phosphorylation-dependent cyclin O transcription. Moreover, myeloid Slc6a14 deficiency alleviates pulmonary inflammation via suppressing inflammatory macrophage responses. Overall, these results uncover a network by which SLC6A14-mediated asparagine uptake orchestrates macrophage inflammation through histone phosphorylation, providing a crucial target for modulation of inflammatory diseases.
    DOI:  https://doi.org/10.1126/sciadv.ads3506
  17. Free Radic Biol Med. 2025 Apr 02. pii: S0891-5849(25)00204-7. [Epub ahead of print]
    Oxidative stress and central metabolism pathways impact epigenetic modulation in inflammation and immune response.
    José Luis García-Giménez, Irene Cánovas-Cervera, Elena Nacher-Sendra, Enric Dolz-Andrés, Álvaro Sánchez-Bernabéu, Ana Belén Agúndez, Javier Hernández-Gil, Salvador Mena-Mollá, Federico V Pallardó.
      Oxidative stress, metabolism, and epigenetics are deeply interconnected processes that collectively influence cellular function, health status, and contribute to disease progression. This review highlights the critical role of metabolic intermediates in epigenetic regulation, focusing on lactate, glutathione (GSH), and S-adenosylmethionine (SAM). Beyond its traditional role in energy metabolism, lactate modulates epigenetic mechanisms, influencing gene expression and cellular adaptation. Meanwhile, GSH and SAM serve as key regulators of DNA methylation and histone post-translational modifications, maintaining epigenetic homeostasis. These processes are tightly controlled by redox balance and oxidative stress, underscoring the intricate interplay between metabolism and epigenetic regulation. GSH depletion disrupts methylation homeostasis, while oxidative post-translational modifications (oxPTMs) on histones-including S-glutathionylation, carbonylation, and nitrosylation-alter chromatin architecture and transcriptional regulation. dditionally, we focus on histone lactylation, particularly its role in regulating innate and adaptive immune responses. We also explore how GSH and oxidative stress influence lactate levels, potentially inducing histone lactylation or S-glutathionylation through S,D-lactoylglutathione (LGSH), thereby impacting epigenetic regulation. By integrating insights into metabolic-epigenetic crosstalk, this review underscores the role of oxidative stress and central metabolic pathways in regulating epigenetic mechanisms, a concept known as "redox epigenetics." Understanding these intricate interactions offers new perspectives for therapeutic strategies aimed at restoring redox homeostasis and metabolic integrity to counteract disturbances in the epigenetic landscape.
    Keywords:  Epigenetics; Histone lactylation; Immune regulation; Inflammation; Oxidative Stress; Oxidative post-translational modifications (oxPTMs)
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.004
  18. Gene. 2025 Apr 04. pii: S0378-1119(25)00257-4. [Epub ahead of print]955 149469
    Genetic and immunological regulation of gut Microbiota: The Roles of TLRs, CLRs, and key proteins in microbial homeostasis and disease.
    Marylyn Ayoub, Yara Abi Chmouni, Norman Damaa, Alaa Eter, Hilmi Medawar, Hilda E Ghadieh, Samer Bazzi, Ziad Abi Khattar, Sami Azar, Frederic Harb.
      The gut microbiota plays a crucial role in human health, influencing metabolism, immune regulation, and neurological function. This review examines the genetic and immunological mechanisms governing microbiota composition, with a focus on key pattern recognition receptors, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and signaling proteins such as CARD9 and NOD2. We discuss how genetic polymorphisms in these receptors contribute to gut dysbiosis and disease susceptibility, particularly in inflammatory bowel disease (IBD) and neurodegenerative disorders like Parkinson's disease. Additionally, we explore emerging microbiota-targeted therapeutic strategies, including probiotics and precision medicine approaches. By synthesizing recent advancements, this review examines how genetic and immunological mechanisms regulate gut microbiota and influence disease susceptibility, emphasizing key therapeutic implications.
    Keywords:  Card9; Clec7A; Gut microbiota; Gut-microbiota-brain axis; Immune system; Parkinson’s disease; Toll-like receptors; mycobiota, DEFB-1
    DOI:  https://doi.org/10.1016/j.gene.2025.149469
  19. Dev Cell. 2025 Apr 07. pii: S1534-5807(25)00066-8. [Epub ahead of print]60(7): 982-993
    Mechanisms of ferroptosis sensitization and resistance.
    Weaverly Colleen Lee, Scott J Dixon.
      Ferroptosis is an iron-dependent and oxidative form of non-apoptotic cell death with roles in development, homeostasis, and disease. Ferroptosis sensitivity can vary between cells, often for reasons that are not well understood. In this perspective, we describe the core ferroptosis mechanism and outline how changes in iron, redox, and lipid metabolism can alter ferroptosis sensitivity. We propose the concept of a ferroptosis sensitivity-resistance continuum to describe how different intrinsic and extrinsic factors interact to push cells toward a more ferroptosis-sensitive or ferroptosis-resistant state, with effects on development and diseases such as cancer.
    Keywords:  GPX4; cancer; development; ferroptosis; glutathione; iron; lipid peroxidation; necrosis; neurodegeneration; system xc(−)
    DOI:  https://doi.org/10.1016/j.devcel.2025.02.004
  20. bioRxiv. 2025 Mar 25. pii: 2025.03.24.645052. [Epub ahead of print]
    Gut bacterial lactate stimulates lung epithelial mitochondria and exacerbates acute lung injury.
    Vaibhav Upadhyay, Edwin F Ortega, Luis A Ramirez Hernandez, Margaret Alexander, Gagandeep Kaur, Kai Trepka, Rachel R Rock, Rafaella T Shima, W Colby Cheshire, Narges Alipanah-Lechner, Carolyn S Calfee, Michael A Matthay, Joyce V Lee, Andrei Goga, Isha H Jain, Peter J Turnbaugh.
      Acute respiratory distress syndrome (ARDS) is an often fatal critical illness where lung epithelial injury leads to intrapulmonary fluid accumulation. ARDS became widespread during the COVID-19 pandemic, motivating a renewed effort to understand the complex etiology of this disease. Rigorous prior work has implicated lung endothelial and epithelial injury in response to an insult such as bacterial infection; however, the impact of microorganisms found in other organs on ARDS remains unclear. Here, we use a combination of gnotobiotic mice, cell culture experiments, and re-analyses of a large metabolomics dataset from ARDS patients to reveal that gut bacteria impact lung cellular respiration by releasing metabolites that alter mitochondrial activity in lung epithelium. Colonization of germ-free mice with a complex gut microbiota stimulated lung mitochondrial gene expression. A single human gut bacterial species, Bifidobacterium adolescentis, was sufficient to replicate this effect, leading to a significant increase in mitochondrial membrane potential in lung epithelial cells. We then used genome sequencing and mass spectrometry to confirm that B. adolescentis produces L -lactate, which was sufficient to increase mitochondrial activity in lung epithelial cells. Finally, we found that serum lactate was significantly associated with disease severity in patients with ARDS from the Early Assessment of Renal and Lung Injury (EARLI) cohort. Together, these results emphasize the importance of more broadly characterizing the microbial etiology of ARDS and other lung diseases given the ability of gut bacterial metabolites to remotely control lung cellular respiration. Our discovery of a single bacteria-metabolite pair provides a proof-of-concept for systematically testing other microbial metabolites and a mechanistic biomarker that could be pursued in future clinical studies. Furthermore, our work adds to the growing literature linking the microbiome to mitochondrial function, raising intriguing questions as to the bidirectional communication between our endo- and ecto-symbionts.
    DOI:  https://doi.org/10.1101/2025.03.24.645052
  21. Microbiome Res Rep. 2025 ;4(1): 7
    Mobile genetic elements: the hidden puppet masters underlying infant gut microbiome assembly?
    Kim Kreuze, Ville-Petri Friman, Tommi Vatanen.
      The gut microbiota is important for healthy infant development. Part of the initial colonizing microbial strains originate from the maternal gut, and undergo a selective event, termed the "colonization bottleneck". While vertical mother-to-infant inheritance and subsequent colonization of bacteria have previously been studied, the role of mobile genetic elements (MGEs) in the infant gut microbiota assembly is unclear. In this perspective article, we discuss how horizontally and vertically transmitted phages and conjugative elements potentially have important roles in infant gut microbiota assembly and colonization through parasitic and mutualistic interactions with their bacterial hosts. While some of these MGEs are likely to be detrimental to their host survival, in other contexts, they may help bacteria colonize new niches, antagonize other bacteria, or protect themselves from other parasitic MGEs in the infant gut. As a result, the horizontal transfer of MGEs likely occurs at high rates in the infant gut, contributing to gene transfer between bacteria and affecting which bacteria can pass the colonization bottleneck. We conclude by highlighting the potential in silico, in vitro, and in vivo methodological approaches that could be employed to study the transmission and colonization dynamics of MGEs and bacteria in the infant gut.
    Keywords:  Colonization bottleneck; MGEs; horizontal transmission; infant gut microbiome; phage; phage-plasmid; plasmid
    DOI:  https://doi.org/10.20517/mrr.2024.51
  22. Front Immunol. 2025 ;16 1520814
    Mitochondrial dynamics at the intersection of macrophage polarization and metabolism.
    Pan Li, Zhengbo Fan, Yanlan Huang, Liang Luo, Xiaoyan Wu.
      Macrophages are vital sentinels in innate immunity, and their functions cannot be performed without internal metabolic reprogramming. Mitochondrial dynamics, especially mitochondrial fusion and fission, contributes to the maintenance of mitochondrial homeostasis. The link between mitochondrial dynamics and macrophages in the past has focused on the immune function of macrophages. We innovatively summarize and propose a link between mitochondrial dynamics and macrophage metabolism. Among them, fusion-related FAM73b, MTCH2, SLP-2 (Stomatin-like protein 2), and mtSIRT, and fission-related Fis1 and MTP18 may be the link between mitochondrial dynamics and macrophage metabolism association. Furthermore, post-translational modifications (PTMs) of mtSIRT play prominent roles in mitochondrial dynamics-macrophage metabolism connection, such as deacetylates and hypersuccinylation. MicroRNAs such as miR-150, miR-15b, and miR-125b are also possible entry points. The metabolic reprogramming of macrophages through the regulation of mitochondrial dynamics helps improve their adaptability and resistance to adverse environments and provides therapeutic possibilities for various diseases.
    Keywords:  fission; fusion; macrophage; metabolism; mitochondrial dynamics
    DOI:  https://doi.org/10.3389/fimmu.2025.1520814
  23. J Control Release. 2025 Apr 04. pii: S0168-3659(25)00322-0. [Epub ahead of print]382 113702
    Pathogen-targeting biomineralized bacterial outer membrane vesicles for eradicating both intracellular and extracellular Staphylococcus aureus.
    Xiaohong Yang, Gongming Shi, Zihua Lin, Yanfei Qiu, Feiyang Liu, Kecui Hu, Jian Guo, Haibo Peng, Yun He.
      Intracellular Staphylococcus aureus is associated with recurrent infections and antibiotic resistance. Conventional antibiotics are ineffective against such intracellular bacterial pathogens, which calls for exploration of new approaches to treat these infections. Here, we report the development of pathogen-targeting biomineralized bacterial outer membrane vesicle (OMV) for targeted antibiotic delivery and eradicating both intracellular and extracellular S. aureus. These OMVs were derived from E. coli, and chemically modified with hydroxamate-type siderophore to target the intracellular S. aureus. The surface of OMV was coated with pH-sensitive calcium carbonate (CaCO3) to target the infection microenvironment. The CaCO3-coated siderophore-OMV (SOMV@CaCO3) was loaded with the antimicrobial drugs lysostaphin (Lsn) and mupirocin (Mup) (Lsn-SOMV@CaCO3-Mup) and administration of these OMVs resulted in effective eradication of both extracellular and intracellular S. aureus. Thus, Lsn-SOMV@CaCO3-Mup provides a novel and promising strategy for the treatment of invasive S. aureus infections.
    Keywords:  Hydroxamate-type siderophore; Intracellular and extracellular infection; Mineralization; Outer membrane vesicles
    DOI:  https://doi.org/10.1016/j.jconrel.2025.113702
  24. J Adv Res. 2025 Apr 05. pii: S2090-1232(25)00214-0. [Epub ahead of print]
    When glycobiology meets inflammasome activation: Insights and implications.
    Hongliang Zhang, Tengchuan Jin, Mengzhou Xue, Songquan Wu, Chunfu Zheng.
       BACKGROUND: Glycobiology focuses mainly on the study of glycan structures and their biological functions. Glycans not only provide a basic energy supply through the tricarboxylic acid cycle and glycolysis but also serve as important immune regulators during pathogen invasion and homeostasis maintenance. Inflammasomes are critical multiprotein complexes of the immune system that detect both exogenous pathogenic threats and endogenous danger signals to mediate inflammatory responses. Glycobiology has revealed significant insights into the mechanisms of immune responses, particularly in the context of inflammasome activation.
    AIM OF REVIEW: This review summarizes the multifaceted relationships between glycobiology and inflammasome activation, highlighting how glycan structures, glycosylation patterns, and glycan-binding proteins influence inflammasome pathways. This review sheds light on novel targets for drug development aimed at modulating inflammatory pathways through the targeting of specific glycan structures.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: Glycans directly or indirectly provide prime and activation signals for inflammasomes, glycosylation of inflammasome-related proteins by glycan structures modulates inflammasome activation and downstream inflammation, and the interaction between glycans and lectins also provides regulatory signals for inflammasome activation. This intersection of glycobiology and inflammasome activation presents a unique opportunity to elucidate the molecular mechanisms underlying inflammatory responses and their potential therapeutic implications.
    Keywords:  Glycans; Glycosylation; Inflammasome; NLRP3; TLRs
    DOI:  https://doi.org/10.1016/j.jare.2025.03.054
  25. Immunol Invest. 2025 Apr 11. 1-27
    Macrophage Polarization in Lung Diseases: From Mechanisms to Therapeutic Strategies.
    Jia Wang, Huajie Niu, Junwei Kang, Haiping Liu, Xiaoyang Dong.
      Macrophages are pivotal immune cells involved in maintaining immune homeostasis and defending against pathogens. They exhibit significant plasticity and heterogeneity, enabling polarization into pro-inflammatory M1 or anti-inflammatory M2 phenotypes in response to distinct microenvironmental cues. The process of macrophage polarization is tightly regulated by complex signaling pathways and transcriptional networks. This review explores the factors influencing macrophage polarization, the associated signaling pathways, and their roles in the pathogenesis of lung diseases, including fibrosis, cancer, and chronic inflammatory conditions. By summarizing recent advances, we aim to provide insights into the immunoregulatory functions of macrophages and their therapeutic potential. Based on our review, it is believed that targeting macrophage polarization emerges as a promising approach for developing effective treatments for lung diseases, balancing inflammation and repair while mitigating disease progression.
    Keywords:  Lung diseases; macrophage polarization; signal pathway
    DOI:  https://doi.org/10.1080/08820139.2025.2490898
  26. Autophagy. 2025 Apr 07.
    TFEB and TFE3 regulate STING1-dependent immune responses by controlling type I interferon signaling.
    Pablo J Tapia, José A Martina, Pablo S Contreras, Akriti Prashar, Eutteum Jeong, Dominic De Nardo, Rosa Puertollano.
      STING1 is an essential component of the innate immune defense against a wide variety of pathogens. Whereas induction of type I interferon (IFN) responses is one of the best-defined functions of STING1, our transcriptomic analysis revealed IFN-independent activities of STING1 in macrophages, including transcriptional upregulation of numerous lysosomal and autophagic genes. This upregulation was mediated by the STING1-induced activation of the transcription factors TFEB and TFE3, and led to increased autophagy, lysosomal biogenesis, and lysosomal acidification. TFEB and TFE3 also modulated IFN-dependent STING1 signaling by controlling IRF3 activation. IFN production and cell death were increased in TFEB- and TFE3-depleted iBMDMs. Conversely, TFEB overexpression led to reduced IRF3 activation and an almost complete inhibition of IFN synthesis and secretion, resulting in decreased CASP3 activation and increased cell survival. Our study reveals a key role of TFEB and TFE3 as regulators of STING1-mediated innate antiviral immunity.
    Keywords:  Autophagy; STING1; TFE3; TFEB; immune response; lysosomes
    DOI:  https://doi.org/10.1080/15548627.2025.2487036
  27. Front Immunol. 2025 ;16 1542438
    Dynamic regulation of neutrophil immunometabolism by platelet-derived metabolites.
    Manuel Alejandro Mosso-Pani, Dante Barreda, Ma Isabel Salazar.
      Platelets, traditionally known for their roles in hemostasis and thrombosis, have emerged as key regulators of immune responses, particularly through their dynamic interactions with neutrophils. This review explores how platelets influence neutrophil functions by forming platelet-neutrophil aggregates, releasing extracellular vesicles, and secreting metabolites. These processes govern critical immune activities, including cell recruitment, activation, endothelium interactions and the resolution or exacerbation of inflammation. Additionally, platelets induce metabolic reprogramming in neutrophils, affecting glycolysis and mitochondrial pathways, while also shaping the immune microenvironment by modulating other immune cells, such as T and B cells. Understanding this complex crosstalk between platelets and neutrophils-two of the most abundant cell types in the bloodstream-might reveal new therapeutic opportunities to regulate immune responses in inflammatory and immune-mediated diseases.
    Keywords:  inflammation regulation; mitochondrial metabolism; neutrophil immunometabolism; platelet-derived metabolites; platelet-neutrophil aggregates
    DOI:  https://doi.org/10.3389/fimmu.2025.1542438
  28. Nat Microbiol. 2025 Apr 11.
    Host AAA-ATPase VCP/p97 lyses ubiquitinated intracellular bacteria as an innate antimicrobial defence.
    Sourav Ghosh, Suvapriya Roy, Navin Baid, Udit Kumar Das, Sumit Rakshit, Paulomi Sanghavi, Dipasree Hajra, Sayani Das, Sneha Menon, Mohammad Sahil, Sudipti Shaw, Raju S Rajmani, Harikrishna Adicherla, Sandip Kaledhonkar, Jagannath Mondal, Dipshikha Chakravortty, Roop Mallik, Anirban Banerjee.
      Cell-autonomous immunity prevents intracellular pathogen growth through mechanisms such as ubiquitination and proteasomal targeting of bacteria for degradation. However, how the proteasome eradicates ubiquitinated bacteria has remained unclear. Here we show that host AAA-ATPase, VCP/p97, associates with diverse cytosol-exposed ubiquitinated bacteria (Streptococcus pneumoniae, Salmonella enterica serovar Typhimurium, Streptococcus pyogenes) and requires the ATPase activity in its D2 domain to reduce intracellular bacterial loads. Combining optical trap approaches along with molecular dynamic simulations, in vitro reconstitution and immunogold transmission electron microscopy, we demonstrate that p97 applies mechanical force to extract ubiquitinated surface proteins, BgaA and PspA, from S. pneumoniae cell membranes. This causes extensive membrane lysis and release of cytosolic content, thereby killing the pathogen. Further, p97 also controls S. pneumoniae proliferation in mice, ultimately protecting from fatal sepsis. Overall, we discovered a distinct innate antimicrobial function of p97 that can protect the host against lethal bacterial infections.
    DOI:  https://doi.org/10.1038/s41564-025-01984-y
  29. J Biosci. 2025 ;pii: 25. [Epub ahead of print]50
    Immune responses in the skin: Not so skinny at all.
    Dipankar Nandi, Nikita S Ramteke.
      The immune system is our defence network and primarily geared to protect us from pathogens and tumors. This aspect is evident in people who lack or possess a compromised immune system and are, therefore, highly susceptible to infections and development of cancer, as in AIDS patients (Nandi et al. 2020). However, healthy humans possess commensals in the gut and have developed a symbiotic relationship with these microbes. Indeed, we benefit from gut microbes that reside within us due to the production of microbial products such as vitamins, short-chain fatty acids, and other metabolites. As the gut flora changes with disease, information on the changed microbiome can be highly reflective of our health status (Shreiner et al. 2015). Recently, efforts have been directed towards better understanding of host responses towards commensals. While it is true that most of these efforts have focused on the gut, other organs have also been studied such as the respiratory tract and oral cavities. Two new studies have shed light on immune responses in the skin (Bousbaine et al. 2024; Gribonika et al. 2024). Why the skin? In fact, the skin is the largest and most well-exposed organ harboring immune capabilities to deal with several commensals (Belkaid and Segre 2014; Honda et al. 2019; Zhang et al. 2022). Most importantly, bacteria obtained from the skin in healthy humans are coated with antibodies, demonstrating host-directed immune responses (Metze et al. 1991); also, immunodeficient people are susceptible to skin infections (Lehman 2014). However, a detailed understanding of the players involved, and the extent of skin-directed immune responses in dealing with various microbes are lacking. Two recent papers have shed new light on immune responses in the skin utilizing high end flow cytometry, several strains of mutant mice and RNA seq (Bousbaine et al. 2024; Gribonika et al. 2024).
  30. Eur J Med Res. 2025 Apr 07. 30(1): 248
    The metabolites of gut microbiota: their role in ferroptosis in inflammatory bowel disease.
    Jingying Zhou, Penghui Lu, Haolong He, Ruhan Zhang, Dican Yang, Qiong Liu, Qianyan Liu, Mi Liu, Guoshan Zhang.
      Inflammatory bowel disease (IBD) includes chronic inflammatory conditions, such as Crohn's disease and ulcerative colitis, characterized by impaired function of the intestinal mucosal epithelial barrier. In recent years, ferroptosis, a novel form of cell death, has been confirmed to be involved in the pathological process of IBD and is related to various pathological changes, such as oxidative stress and inflammation. Recent studies have further revealed the complex interactions between the microbiome and ferroptosis, indicating that ferroptosis is an important target for the regulation of IBD by the gut microbiota and its metabolites. This article reviews the significant roles of gut microbial metabolites, such as short-chain fatty acids, tryptophan, and bile acids, in ferroptosis in IBD. These metabolites participate in the regulation of ferroptosis by influencing the intestinal microenvironment, modulating immune responses, and altering oxidative stress levels, thereby exerting an impact on the pathological development of IBD. Treatments based on the gut microbiota for IBD are gradually becoming a research hotspot. Finally, we discuss the potential of current therapeutic approaches, including antibiotics, probiotics, prebiotics, and fecal microbiota transplantation, in modulating the gut microbiota, affecting ferroptosis, and improving IBD symptoms. With a deeper understanding of the interaction mechanisms between the gut microbiota and ferroptosis, it is expected that more precise and effective treatment strategies for IBD will be developed in the future.
    Keywords:  Ferroptosis; Gut microbiota; Inflammatory bowel disease; Short-chain fatty acids
    DOI:  https://doi.org/10.1186/s40001-025-02524-4
  31. J Biochem. 2025 Apr 08. pii: mvaf016. [Epub ahead of print]
    Innate immune signals triggered on organelle membranes.
    Yoshihiko Kuchitsu, Tomohiko Taguchi.
      Our body is constantly exposed to pathogens, and equipped with a highly elaborate immune system to fight against invading pathogens. The first line of defense is the innate immune system. It has evolved to detect conserved microbial molecular patterns, dubbed pathogen-associated molecular patterns (PAMPs), through pattern recognition receptors (PRRs). The binding of PRRs to PAMPs activates intracellular signalling cascades that lead to the expression of proinflammatory cytokines, type I interferons, and other antiviral proteins that all coordinate the elimination of pathogens and infected cells. PRRs can be classified as transmembrane receptors, including Toll-like receptors (TLRs) and some C-type lectin receptors (CLRs), and as cytosolic receptors including retinoic acid-inducible gene-I (RIG-I)-like receptors, nucleotide-binding domain and leucine-rich repeat-containing (NLR) proteins, and cyclic GMP-AMP (cGAMP) synthase (cGAS). Studies have revealed that innate immune signals, including the ones activated by cytosolic PRRs, are triggered on organelle membranes. Here we review the recent insights into how organelle membranes and their associated membrane lipids contribute to PRR-mediated innate immune signals.
    Keywords:  inflammasome; innate immunity; organelle membrane; phospholipid; protein palmitoylation
    DOI:  https://doi.org/10.1093/jb/mvaf016
  32. Respir Res. 2025 Apr 09. 26(1): 131
    Early secretory antigen target of 6-kDa of Mycobacterium tuberculosis inhibits macrophage apoptosis and host defense via TLR2.
    Lin Zhang, Fang Fang, Danrui Liu, Geman Xia, Tong Feng, Jingzhu Lv, Jinying Qi, Tengteng Li, Hui Liu, Tao Xu, Fengjiao Wu, Chuanwang Song, Wei Li, Xiaojing Wang, Xianyou Chang, Hongtao Wang, Ting Wang, Zhongqing Qian.
      Mycobacterium tuberculosis (M. tb) is an intracellular pathogen adept at evading the human immune system through a variety of mechanisms. During infection, M. tb secretes numerous virulence factors, including the 6 kDa early secretory antigen target (ESAT-6), which is produced by the ESX-1 secretion system. ESAT-6 plays a crucial role in host-pathogen interactions, either independently or in association with culture filtrate protein 10 (CFP-10). While some research has investigated the role of ESAT-6 in M. tb pathogenicity and vaccine development, its precise contribution to immune evasion and the cellular mechanisms involved remain poorly understood. To address this, we used cultured THP-1(A) macrophages to characterize the effects of secreted ESAT-6 on cellular host defenses and apoptosis. We found that ESAT-6 (5 μg/ml) inhibited M. tb-induced apoptosis in THP-1(A) macrophages by suppressing Toll-like receptor 2 (TLR2) through the Caspase-9/Caspase-3 pathway. Additionally, ESAT-6 reduced phagocytosis of M. tb by THP-1(A) macrophages by downregulating the production of interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and interleukin-12 (IL-12). Furthermore, ESAT-6 diminished the bactericidal activity of macrophages by inducing reactive oxygen species (ROS) production. In parallel, our in silico analysis of differentially expressed genes in dendritic cells (DCs) infected with Bacille Calmette-Guérin (BCG) strains, with or without the region of difference-1 (RD1) gene, strongly suggests that ESAT-6, located within the RD1 region, modulates host defense functions and apoptosis in DCs during BCG infection. Collectively, these findings indicate that ESAT-6 plays a pivotal role in modulating the innate immune response of macrophages against M. tb by regulating macrophage recognition, phagocytosis, bactericidal activity, and apoptosis. Our study provides valuable insights into potential molecular targets for the development of innovative vaccines and therapeutic strategies against M. tb.
    Keywords:   M. tb ; Apoptosis; ESAT-6; Macrophage; TLR2
    DOI:  https://doi.org/10.1186/s12931-025-03210-z
  33. Semin Immunol. 2025 Apr 09. pii: S1044-5323(25)00025-9. [Epub ahead of print]78 101953
    Cellular stress and macrophage activation.
    Jing Yu, Bin-Zhi Qian.
      Cellular stress responses are pivotal in maintaining tissue homeostasis and intricately linked with various diseases. Macrophages, a key player of innate immune system, exhibit remarkable plasticity and responsiveness to environmental cues. In response to various cellular stresses, macrophages contribute to tissue homeostasis and disease progression via specialized activation/polarization associated with distinctive phenotypes and functions. This review provides an overview of the intricate interplay between cellular stress responses and macrophage activation, summarizing recent advancements and offering insights into potential therapeutic strategies.
    Keywords:  Cellular stress response; Immune response; Macrophage
    DOI:  https://doi.org/10.1016/j.smim.2025.101953
  34. NPJ Antimicrob Resist. 2025 Apr 04. 3(1): 24
    Metabolic state-driven nutrient-based approach to combat bacterial antibiotic resistance.
    Bo Peng, Hui Li, Xuan-Xian Peng.
      To combat antibiotic resistance, one innovative approach, known as the metabolic state-driven approach, exploits the fact that exogenous nutrient metabolites can stimulate uptake of antibiotics. The most effective nutrient metabolites are identified by comparing metabolic states between antibiotic-sensitive and -resistant bacteria. When bacteria are exposed to the specific nutrient metabolites, they undergo a form of metabolic reprogramming. This review summarizes the recent progress on the metabolic state-driven approach.
    DOI:  https://doi.org/10.1038/s44259-025-00092-5
  35. bioRxiv. 2025 Mar 26. pii: 2025.03.25.645303. [Epub ahead of print]
    CFTR function in alveolar type 1 cells drives lung liquid secretion and host defense.
    Sayahi Suthakaran, Sonya Homami, Deebly Chavez, Stephanie Tang, Sarah K L Moore, Chaya Sussman, Jimmy Zhang, Clemente J Britto, Alice Prince, Alison J May, Jaymin J Kathiriya, Jaime L Hook.
      Loss of the liquid layer that lines the lung's air-facing surface underpins mechanisms of major lung diseases, but the development of therapies that restore liquid secretion is hampered by an incomplete understanding of the cell types that drive it. Here, we show CFTR function in alveolar type 1 (AT1) cells - a cell type that comprises 95% of the lung surface but is presumed to be unimportant in CFTR-related diseases - is critical to lung liquid secretion and the secretion-mediated clearance of particles and S. aureus from lung alveoli. Our findings reveal essential roles for AT1 cells in lung homeostasis and defense, and they call for a reevaluation of the role of AT1 cells in CFTR-related diseases. We suggest AT1 cells be considered key targets of secretion-restoring therapies.
    DOI:  https://doi.org/10.1101/2025.03.25.645303
  36. Eur J Med Res. 2025 Apr 11. 30(1): 271
    M2 macrophage-derived exosomes reverse TGF-β1-induced epithelial mesenchymal transformation in BEAS-2B cells via the TGF-βRI/Smad2/3 signaling pathway.
    Chao Liu, Xiaolin Huang, Siqi Li, Wentao Ji, Tian Luo, Jianping Liang, Yanhua Lv.
       INTRODUCTION: Airway remodeling in bronchial asthma can be inhibited by disrupting the epithelial mesenchymal transition (EMT) of activated airway epithelial cells. Exosomes, as key mediators of intercellular communication, have been implicated in the pathophysiology of asthma-related airway inflammation, remodeling, and hyperresponsiveness. This study aimed to investigate the role of M2 macrophage-derived exosomes (M2φ-exos) in modulating TGF-β1-induced EMT in airway epithelial (BEAS-2B) cells and elucidate the underlying molecular mechanism, if any.
    METHODS: THP-1 cells were induced to differentiate into M2 macrophages via phorbol 12-myristate 13-acetate (PMA) and IL-4. Exosomes were subsequently isolated and purified via ultracentrifugation. M2φ-exos expression was characterized by protein marker levels, transmission electron microscopy imaging, and nanoparticle tracking analysis. TGF-β1-induced BEAS-2B cells were exposed to M2φ-exos to determine the latter's effects.
    RESULTS: THP-1 cells were successfully differentiated into M2 macrophages, as confirmed by in vitro flow cytometry. The isolated exosomes presented typical cup-shaped structures and expressed CD81 and TSG101. TGF-β1 induction altered the morphological characteristics of BEAS-2B cells and activated the TGF-βRI/Smad2/3 signaling pathway, leading to increased expression of Snail, Vimentin and Collagen 1 and decreased expression of E-cadherin. After exosome or SB431542 induction, TGF-β1-induced EMT was reversed. GW4869, an exosome release inhibitor, exhibited the ability to block the beneficial effects of exosomes.
    CONCLUSION: M2Φ-exos inhibited EMT in BEAS-2B cells through the TGF-βRI/Smad2/3 signaling pathway. This novel insight into the role of M2Φ-exos in modulating EMT may have important implications for the beneficial effects of asthma, particularly in addressing airway remodeling.
    Keywords:  Airway epithelial cells; Airway remodeling; Epithelial mesenchymal transformation; Exosomes; Macrophages
    DOI:  https://doi.org/10.1186/s40001-025-02516-4
  37. Cell Host Microbe. 2025 Apr 09. pii: S1931-3128(25)00057-5. [Epub ahead of print]33(4): 457-458
    Mucosal stargazing: IgA keeps astrovirus in check.
    Tim Rollenske.
      Immunoglobulin A (IgA) antibodies maintain homeostasis between the host and its microbiota, by exerting luminal control over fungi and bacteria. In this issue of Cell Host & Microbe, Lisicka et al. show that IgA antibodies also control the population of specific members of our virome.
    DOI:  https://doi.org/10.1016/j.chom.2025.02.009
  38. JCI Insight. 2025 Apr 10. pii: e189330. [Epub ahead of print]
    The PERK-ATF4 pathway is required for metabolic reprogramming and progressive lung fibrosis.
    Jyotsana Pandey, Jennifer L Larson-Casey, Mallikarjun H Patil, Chao He, Nisarat Pinthong, A Brent Carter.
      Asbestosis is a prototypical type of fibrosis that is progressive and does not resolve. ER stress is increased in multiple cell types that contribute to fibrosis; however, the mechanism(s) by which ER stress in lung macrophages contributes to fibrosis is poorly understood. Here, we show that ER stress resulted in PERK activation in human subjects with asbestosis. Similar results were seen in asbestos-injured mice. Mice harboring a conditional deletion of Eif2ak3 were protected from fibrosis. Lung macrophages from asbestosis subjects had evidence of metabolic reprogramming to fatty acid oxidation (FAO). Eif2ak3fl/fl mice had increased oxygen consumption rate (OCR), whereas OCR in Eif2ak3-/-Lyz2-cre mice was reduced to control levels. PERK increased Atf4 expression, and ATF4 bound to the Ppargc1a promoter to increase its expression. GSK2656157, a PERK-specific inhibitor, reduced FAO, Ppargc1a, and Aft4 in lung macrophages and reversed established fibrosis in mice. These observations suggest that PERK is a unique therapeutic target to reverse established fibrosis.
    Keywords:  Fatty acid oxidation; Fibrosis; Immunology; Macrophages; Pulmonology
    DOI:  https://doi.org/10.1172/jci.insight.189330
  39. PLoS Pathog. 2025 Apr 08. 21(4): e1013054
    Identification of the Pseudomonas aeruginosa AgtR-CspC-RsaL pathway that controls Las quorum sensing in response to metabolic perturbation and Staphylococcus aureus.
    Junze Qu, Liwen Yin, Shanhua Qin, Xiaomeng Sun, Xuetao Gong, Shouyi Li, Xiaolei Pan, Yongxin Jin, Zhihui Cheng, Shouguang Jin, Weihui Wu.
      Environmental metabolites and metabolic pathways significantly influence bacterial pathogenesis and interspecies competition. We previously discovered that a mutation in the triosephosphate isomerase gene, tpiA, in Pseudomonas aeruginosa led to defective type III secretion and increased susceptibility to aminoglycoside antibiotics. In this study, we found that the tpiA mutation enhances the Las quorum sensing system due to reduced translation of the negative regulator RsaL. Further investigations demonstrated an upregulation of CspC, a CspA family protein that represses rsaL translation. DNA pull-down assay, along with genetic studies, revealed the role of AgtR in regulating cspC transcription. AgtR is known to regulate pyocyanin production in response to N-acetylglucosamine (GlcNAc), contributing to competition against Staphylococcus aureus. We demonstrated that CspC activates the Las quorum sensing system and subsequent pyocyanin production in response to GlcNAc and S. aureus. Overall, our results elucidate the AgtR-CspC-RsaL-LasI pathway that regulates bacterial virulence factors and its role in competition against S. aureus.
    DOI:  https://doi.org/10.1371/journal.ppat.1013054
  40. Int J Pharm. 2025 Apr 07. pii: S0378-5173(25)00409-0. [Epub ahead of print]675 125572
    Plant-made trained immunity-based vaccines: Beyond one approach.
    Elizabeth Monreal-Escalante, Miriam Angulo, Abel Ramos-Vega, Edgar Trujillo, Carlos Angulo.
      Plant-made vaccines and trained immunity-based vaccines (TIbV or TRAIMbV) represent two strategies for enhancing immunity against diseases. Plants provide an effective and cost-efficient vaccine production platform, while TIbV induces innate immune memory that can protect against both homologous and heterologous diseases. Both strategies are generally compatible; however, they have not been explored in a transdisciplinary manner. Despite their strengths in vaccinology, each faces limitations that hinder widespread adoption and health benefits. This review revisits both strategies, discussing their fundamental knowledge alongside practical and experimental examples, ultimately highlighting their limitations and perspectives to pave the way for a unified approach to combat diseases. Future scenarios are envisioned and presented if research on plant-made trained immunity-based vaccines is adopted.
    Keywords:  Green biotherapeutics; Immunization; Infectious; Molecular farming
    DOI:  https://doi.org/10.1016/j.ijpharm.2025.125572
  41. Eur J Med Res. 2025 Apr 04. 30(1): 236
    The impact of environmental factors on respiratory tract microbiome and respiratory system diseases.
    Yutao Ge, Guo Tang, Yawen Fu, Peng Deng, Rong Yao.
      The respiratory tract microbiome, a complex ecosystem of microorganisms colonizing the respiratory mucous layers and epithelial surfaces along with their associated microenvironment, plays a vital role in maintaining respiratory function and promoting the maturation of the respiratory immune system. Current research suggests that environmental changes can disrupt the respiratory microbiota, potentially leading to disease. This review summarizes existing research on the impact of environmental factors on the respiratory microbiome and associated diseases, aiming to offer new insights into the prevention and treatment of respiratory disease.
    Keywords:  Air pollutants; Gut–lung axis; Humidity; Respiratory microbiome; Temperature
    DOI:  https://doi.org/10.1186/s40001-025-02517-3
  42. Cell Oncol (Dordr). 2025 Apr 09.
    Trained immunity alleviates the progression of melanoma during sepsis-associated immunoparalysis.
    Lijie Yin, Yue Dong, Renjie Luo, Jingman Li, Jiali Wang, Huan Dou, Guangfeng Zhao, Yayi Hou.
       BACKGROUND: Patients who survive the excessive inflammatory phase of sepsis experience prolonged immunoparalysis/immunosuppression. During this phase, the patient's immune system is severely impaired, which increases the patient's susceptibility to septic complications. Sepsis survivors have a significantly greater incidence of cancer, but the mechanism underlying this phenomenon is unknown.
    METHODS: We constructed two sepsis-melanoma models to assess the relationship between sepsis and sepsis-related concomitant cancer. In our investigation, we employed a range of experimental technique to elucidate the intricate mechanisms through which the immunoparalysis phase of sepsis facilitates melanoma progression. Furthermore, we induced trained immunity with oroxylin A (OA) to evaluate its ability to reverse immunoparalysis and subsequent tumor progression in sepsis-melanoma models.
    RESULTS: We showed that sepsis upregulated the serum level of interleukin (IL)-6 and the number of myeloid-derived suppressor cells (MDSCs), regulated G-MDSCs/M-MDSCs and inhibited CD8+T-cell function, which promoted melanoma progression. OA-induced trained immunity can reverse immunoparalysis, maintain the antitumor capacity of the immune system, and inhibit the development of sepsis-complicated melanoma. Notably, OA can target macrophage migration inhibitory factor (MIF) and downregulate the serum level of IL-6, which may be a crucial molecular mechanism by which OA induces trained immunity to reverse the immunoparalysis phase of sepsis.
    CONCLUSION: Sepsis can promote cancer progression by upregulating MIF and IL-6, increasing the G-MDSCs/M-MDSCs ratio and reducing the number and function of CD8+ T cells, leading to immunoparalysis, while trained immunity can alleviate this progression. The findings of this study provide new strategies for preventing or treating sepsis-complicated cancer.
    Keywords:  Immunoparalysis; Melanoma; Oroxylin A; Sepsis; Trained immunity
    DOI:  https://doi.org/10.1007/s13402-025-01063-8
  43. STAR Protoc. 2025 Apr 07. pii: S2666-1667(25)00146-7. [Epub ahead of print]6(2): 103740
    Protocol for microbial profiling of low-biomass upper respiratory tract samples.
    Mari-Lee Odendaal, Mei Ling J N Chu, Kayleigh Arp, Gina J van Beveren, Giske Biesbroek, Justyna Binkowska, Thijs Bosch, James A Groot, Raiza Hasrat, Sjoerd Kuiling, Elske M van Logchem, Paula Lusarreta Parga, Wouter A A de Steenhuijsen Piters, Debby Bogaert.
      The upper respiratory tract (URT) microbiota plays a role in both acute and chronic respiratory health outcomes and consists of multiple ecologically distinct niches, all of which have low bacterial biomass. Here, we present a protocol for microbial profiling of low-biomass URT samples. We describe steps for collecting, storing, and extracting DNA. We then detail procedures for performing 16S rRNA sequencing, using an Illumina MiSeq platform, to characterize microbial communities. For complete details on the use and execution of this protocol, please refer to Odendaal et al.1.
    Keywords:  Bioinformatics; Health Sciences; Microbiology; Molecular Biology; Sequence analysis; Sequencing
    DOI:  https://doi.org/10.1016/j.xpro.2025.103740
  44. Virulence. 2025 Dec;16(1): 2490208
    Staphylococcus aureus β-hemolysin impairs oxygen transport without causing hemolysis.
    Qi Li, Nan Chen, Chenghua Liu, Zhen Zhao, Minjun Huang, Jingjing Li, Guang Yang.
      Staphylococcus aureus (S. aureus) infection can lead to the occurrence of hypoxia, however, the underlying mechanisms have not been fully elucidated. β-hemolysin (Hlb) induced hemolysis of red blood cells (RBCs) requires a temperature transition from "hot" to "cold," a phenomenon not observed under physiological conditions. In this study, we discovered that RBCs treated with Hlb exhibited a high level of intracellular Ca2+ and underwent a shape transformation from biconcave discoid to spherical, which was contingent upon the degradation of sphingomyelin of the cell membrane and led to impaired oxygen transport. The increase in intracellular Ca2+ levels induced by Hlb was dependent on the activation of the ion channel N-methyl-D-aspartate receptor. Furthermore, we found that Hlb-induced Ca2+ influx increased the cytoplasmic pH and subsequently attenuated the oxygen release from RBCs, which were also observed in both hlb transgenic mice and a murine model with S. aureus challenge. Our findings reveal a novel role for Hlb as sphingomyelinase in impairing RBC function under non-lytic conditions, shedding light on the mechanism behind hypoxia associated with S. aureus infection.
    Keywords:  RBC; S. aureus; oxygen release; sphingomyelinase; β-hemolysin
    DOI:  https://doi.org/10.1080/21505594.2025.2490208
  45. Nat Struct Mol Biol. 2025 Apr 04.
    Heritable maintenance of chromatin modifications confers transcriptional memory of interferon-γ signaling.
    Pawel Mikulski, Sahar S H Tehrani, Anna Kogan, Izma Abdul-Zani, Emer Shell, Louise James, Brent J Ryan, Lars E T Jansen.
      Interferon-γ (IFNγ) transiently activates genes related to inflammation and innate immunity. A subset of targets retain a mitotically heritable memory of prior IFNγ exposure, resulting in hyperactivation upon re-exposure through poorly understood mechanisms. Here, we discover that the transcriptionally permissive chromatin marks H3K4me1, H3K14ac and H4K16ac are established during IFNγ priming and are selectively maintained on a cluster of guanylate-binding protein (GBP) genes in dividing human cells in the absence of transcription. The histone acetyltransferase KAT7 is required for H3K14ac deposition at GBP genes and for accelerated GBP reactivation upon re-exposure to IFNγ. In naive cells, the GBP cluster is maintained in a low-level repressive chromatin state, marked by H3K27me3, limiting priming through a PRC2-dependent mechanism. Unexpectedly, IFNγ priming results in transient accumulation of this repressive mark despite active gene expression. However, during the memory phase, H3K27 methylation is selectively depleted from primed GBP genes, facilitating hyperactivation. Furthermore, we identified a cis-regulatory element that forms transient, long-range contacts across the GBP cluster and acts as a repressor, curbing hyperactivation of previously IFNγ-primed cells. Our results provide insight into the chromatin basis for the long-term transcriptional memory of IFNγ signaling, which might contribute to enhanced innate immunity.
    DOI:  https://doi.org/10.1038/s41594-025-01522-8
  46. BBA Adv. 2025 ;7 100156
    Glycan-mediated adhesion mechanisms in antibiotic-resistant bacteria.
    Clara Dessenne, Christophe Mariller, Olivier Vidal, Isabelle Huvent, Yann Guerardel, Elisabeth Elass-Rochard, Yannick Rossez.
      Bacterial adhesins play a central role in host-pathogen interactions, with many specifically targeting glycans to mediate bacterial colonization, influence infection dynamics, and evade host immune responses. In this review, we focus on bacterial pathogens identified by the World Health Organization as critical threats to public health and in urgent need of new treatments. We summarize glycoconjugate targets identified in the literature across 19 bacterial genera and species. This comprehensive review provides a foundation for the development of innovative therapeutic strategies to effectively combat these pathogens.
    Keywords:  Adhesins; Bacteria; Environment; Glycans; Lectin; Pathogens
    DOI:  https://doi.org/10.1016/j.bbadva.2025.100156
  47. Am J Physiol Endocrinol Metab. 2025 Apr 07.
    Roles of Circadian Clocks in Macrophage Metabolism: Implications in Inflammation, and Metabolism of Lipids, Glucose, and Amino Acids.
    Mohammad Irfan Dar, Yusuf Hussain, Xiaoyue Pan.
      Macrophages are essential immune cells that play crucial roles in inflammation and tissue homeostasis, and are important regulators of metabolic processes, such as the metabolism of glucose, lipids, and amino acids. The regulation of macrophage metabolism by circadian clock genes has been emphasized in many studies. Changes in metabolic profiles occurring after the perturbation of macrophage circadian cycles may underlie the etiology of several diseases. Specifically, chronic inflammatory disorders, such as atherosclerosis, diabetes, cardiovascular diseases, and liver dysfunction, are associated with poor macrophage metabolism. Developing treatment approaches that target metabolic and immunological ailments requires an understanding of the complex relationships among clock genes, disease etiology, and macrophage metabolism. This review explores the molecular mechanisms through which clock genes regulate lipid, amino acid, and glucose metabolism in macrophages, and discusses their potential roles in the development and progression of metabolic disorders. The findings underscore the importance of maintaining circadian homeostasis in macrophage function as a promising avenue for therapeutic intervention in diseases involving metabolic dysregulation, given its key roles in inflammation and tissue homeostasis. Moreover, reviewing the therapeutic implications of circadian rhythm in macrophages can help minimize the side effects of treatment. Novel strategies may be beneficial in treating immune-related diseases cause by shifted and blunted circadian rhythms via light exposure, jet lag, seasonal changes, and shift work or disruption to the internal clock (such as stress or disease).
    Keywords:  Circadian clock; Glucose metabolism; Lipid metabolism; Macrophage; inflammation
    DOI:  https://doi.org/10.1152/ajpendo.00009.2025
  48. Front Chem. 2025 ;13 1425666
    Exploring the antimicrobial potential of lactobacilli against early-stage and mature biofilms of Staphylococcus aureus and Pseudomonas aeruginosa.
    Niharika Singh, Rohini Devidas Gulhane, Anamika Singh, Maitri Goel, Pudke Payal Udelal, Vikas Sangwan, Manvesh Kumar Sihag, Gunjan Goel, Harsh Panwar, Anil Kumar Puniya.
      Bacterial biofilms are dynamic, complex, and very adaptive, and they can cause health problems in both humans and animals while also posing a serious threat to various industries. This study explores the potential of cell-free preparations of lactobacilli isolated from breast milk (HM; n = 11) and infant fecal (IF; n = 15) samples to impact the growth of Staphylococcus aureus and Pseudomonas aeruginosa biofilms. The anti-biofilm activity of three distinct cell-free preparations, namely, untreated cell-free supernatant (CFS), pH-neutralized CFS (N-CFS), and heat-treated CFS (H-CFS), was examined against both early-stage and mature biofilms. The post-incubation strategy examined the impact on mature biofilms, while the co-incubation treatment assessed the impact of CFS on adhesion and initial colonization. Compared to post-incubation treatment (HM3, 67.12%), the CFSs exhibited greater inhibitory activity during co-incubation (IF9, 85.19%). Based on the findings, untreated CFS exhibited the most promising biofilm inactivation, although its activity was not completely lost upon pH neutralization and heat treatment. Treatment with H-CFSs and N-CFSs moderately reduced the population of S. aureus and P. aeruginosa bacterial cells within the biofilm by 40%-60%. Microscopic observations showed that after CFS treatment, the integrity of the biofilm conformation was disrupted. According to principal component analysis (PCA) (significance level at p < 0.05), the most promising anti-biofilm activity against both test pathogens was found in the CFS of Lacticaseibacillus paracasei HM1.
    Keywords:  Pseudomonas aeruginosa; Staphylococcus aureus; antimicrobial; biofilm; cell-free supernatant; foodborne pathogens; lactic acid bacteria; probiotics
    DOI:  https://doi.org/10.3389/fchem.2025.1425666
  49. PNAS Nexus. 2025 Apr;4(4): pgaf100
    Polychlorinated biphenyls induce immunometabolic switch of antiinflammatory macrophages toward an inflammatory phenotype.
    Riley M Behan-Bush, Michael V Schrodt, Elizabeth Kilburg, Jesse N Liszewski, Laura M Bitterlich, Karen English, Aloysius J Klingelhutz, James A Ankrum.
      Polychlorinated biphenyls (PCBs) are a group of environmental toxicants associated with increased risk of diabetes, obesity, and metabolic syndrome. These metabolic disorders are characterized by systemic and local inflammation within adipose tissue, the primary site of PCB accumulation. These inflammatory changes arise when resident adipose tissue macrophages undergo phenotypic plasticity-switching from an antiinflammatory to an inflammatory phenotype. Thus, we sought to assess whether PCB exposure drives macrophage phenotypic switching. We investigated how human monocyte-derived macrophages polarized toward an M1, M2a, or M2c phenotype were impacted by exposure to Aroclor 1254, a PCB mixture found at high levels in school air. We showed that PCB exposure not only exacerbates the inflammatory phenotype of M1 macrophages but also shifts both M2a and M2c cells toward a more inflammatory phototype in both a dose- and time-dependent manner. Additionally, we show that PCB exposure leads to significant metabolic changes. M2 macrophages exposed to PCBs exhibit increased reliance on aerobic glycolysis and reduced capacity for fatty acid and amino acid oxidation-both indicators of an inflammatory macrophage phenotype. Collectively, these results demonstrate that PCBs promote immunometabolic macrophage plasticity toward a more M1-like phenotype, thereby suggesting that PCBs exacerbate metabolic diseases by altering the inflammatory environment in adipose tissue.
    Keywords:  PCBs; immunometabolism; plasticity; toxicology
    DOI:  https://doi.org/10.1093/pnasnexus/pgaf100
  50. Life Sci. 2025 Apr 04. pii: S0024-3205(25)00235-8. [Epub ahead of print] 123601
    Reprogram to heal: Macrophage phenotypes as living therapeutics.
    Sheyda Ghamangiz, Abbas Jafari, Hadi Maleki-Kakelar, Hadi Azimi, Ebrahim Mazloomi.
      Macrophages represent a crucial cell type within the immune system, exhibiting significant adaptability that allows for the transformation into various phenotypes in response to their surrounding environment. This review investigates the characteristics of various macrophage phenotypes and their functional roles in disease pathogenesis and resolution. The M1 phenotype, recognized for its inflammatory attributes, plays a pivotal role in combating infections and tumors; however, it may also contribute to tissue injury, persistent inflammation, and the pathogenesis of autoimmune and inflammatory diseases. Conversely, the M2 phenotype is associated with anti-inflammatory activities and tissue repair processes. But this is not the end of the story and researches illustrated novel phenotypes that may provide new approaches and therapeutic opportunities. Recent progress in characterizing distinct macrophage phenotypes has enabled the development of innovative therapeutic strategies for chronic inflammatory conditions, autoimmune disorders, and cancers. This review underscores the critical role of macrophage polarization, illustrating how various stimuli can influence macrophage fate and modify their responses. Additionally, it explores the implications of macrophage plasticity on disease progression and treatment efficacy. A comprehensive understanding of these dynamics is essential for the advancement of targeted immunotherapies, which possess the potential to transform treatment strategies for a variety of medical conditions.
    Keywords:  Inflammation; Macrophages; Phenotypes; Polarization
    DOI:  https://doi.org/10.1016/j.lfs.2025.123601
  51. EMBO Rep. 2025 Apr 09.
    TLR4 endocytosis and endosomal TLR4 signaling are distinct and independent outcomes of TLR4 activation.
    Thomas E Schultz, Carmen D Mathmann, Leslie C Domínguez Cadena, Timothy W Muusse, Hyoyoung Kim, James W Wells, Glen C Ulett, Jessica A Hamerman, Andrew J Brooks, Bostjan Kobe, Matthew J Sweet, Katryn J Stacey, Antje Blumenthal.
      Toll-like receptor 4 (TLR4) signaling at the plasma membrane and in endosomes results in distinct contributions to inflammation and host defence. Current understanding indicates that endocytosis of cell surface-activated TLR4 is required to enable subsequent signaling from endosomes. Contrary to this prevailing model, our data show that endosomal TLR4 signaling is not reliant on cell surface-expressed TLR4 or ligand-induced TLR4 endocytosis. Moreover, previously recognized requirements for the accessory molecule CD14 in TLR4 endocytosis and endosomal signaling are likely attributable to CD14 binding as well as trafficking and transferring lipopolysaccharide (LPS) to TLR4 at different subcellular localizations. TLR4 endocytosis requires the TLR4 intracellular signaling domain, contributions by phospholipase C gamma 2, spleen tyrosine kinase, E1/E2 ubiquitination enzymes, but not canonical TLR signaling adaptors and cascades. Thus, our study identifies independently operating TLR4 signaling modes that control TLR4 endocytosis, pro-inflammatory cell surface-derived, as well as endosomal TLR4 signaling. This revised understanding of how TLR4 functions within cells might be harnessed to selectively amplify or restrict TLR4 activation for the development of adjuvants, vaccines and therapeutics.
    Keywords:  Endosome; LPS; Macrophage; Signaling; TLR4
    DOI:  https://doi.org/10.1038/s44319-025-00444-2
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