bims-bac4me 2025-07-20 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–07–20
nineteen papers selected by
Chun-Chi Chang, Lunds universitet

Targeting alveolar macrophages in tuberculosis: Exploiting trained immunity for novel therapeutic approaches.
Retinoic acid differently modulates NOD1/NOD2-mediated inflammatory responses in human macrophage subsets.
Lantibiotic-producing bacteria impact microbiome resilience and colonization resistance.
SLAMF7 regulates goblet cell mucus production and negatively impacts gut homeostasis and commensalism.
Metabolic regulation of tissue-resident immune cells: Molecular mechanisms and therapeutic implications.
Macrophage clock of pregnancy: circadian and metabolic control of decidual macrophage.
Macrophages as Multifaceted Orchestrators of Tissue Repair: Bridging Inflammation, Regeneration, and Therapeutic Innovation.
Respiratory syncytial virus infection confers heterologous protection against SARS-CoV-2 via induction of γδ T cell-mediated trained immunity and SARS-CoV-2 reactive mucosal T cells.
Deep metabolic profiling of immune cells by spectral flow cytometry-A comprehensive validation approach.
Macrophage Switching in Pregnancy: Regulatory Mechanisms Governing Term Labour and Preterm Birth.
Understanding the probiotic health benefits of Bifidobacterium animalis subsp. lactis, BB-12™.
Short-Term Probiotic Colonization Alters Molecular Dynamics of 3D Oral Biofilms.
Itaconate suppresses neonatal intestinal inflammation via metabolic reprogramming of M1 macrophage.
Lactate and lactylation: emerging roles in autoimmune diseases and metabolic reprogramming.
Mycobacterium bovis frd operon phase variation hijacks succinate signaling to drive immunometabolic rewiring and pathogenicity.
Fungal β-Glucans Shape Innate Immune Responses in Human Peripheral Blood Mononuclear Cells (PBMCs): An In Vitro Study on PRR Regulation, Cytokine Expression, and Oxidative Balance.
Sialylated CD43 is a glyco-immune checkpoint for macrophage phagocytosis.
Narirutin treatment accelerates the process of diabetic wound repair by regulating phenotype switching of macrophages through affecting metabolic reprogramming.
Border-associated macrophages: guardians of vascular homeostasis.

Int Immunopharmacol. 2025 Jul 12. pii: S1567-5769(25)01201-9. [Epub ahead of print]163 115211

Targeting alveolar macrophages in tuberculosis: Exploiting trained immunity for novel therapeutic approaches.

Huilin Fang, Yan Xiong, Beibei Fu, Haibo Wu.

  Tuberculosis (TB) is an airborne infectious disease caused by the Mycobacterium tuberculosis (Mtb) complex organism. Alveolar macrophages (AMs) play key roles in immune defense, antigen presentation, immune regulation, and immune secretion during Mtb infection. Notably, AMs exhibit context-dependent dual functions: protective and pathogenic. This duality is driven by the heterogeneous composition of AM subsets and their distinct immune profiles. On one hand, they fight against Mtb through a series of mechanisms to protect the host; on the other hand, certain AM subsets may provide a permissive niche that facilitates Mtb survival and persistence. Mtb possesses unique cell surface lipids and secreted protein effectors that enable it to evade the killing effects of innate immune cells and preferentially establish an ecological niche within AMs. AMs not only strengthen their antibacterial capabilities through mechanisms such as training immune memory, metabolic reprogramming, cytokine production, and autophagy, but also collaborate with other immune cells to jointly maintain immune balance within the body. Once this balance is disrupted, tuberculosis infection may run rampant. Furthermore, this article summarizes the potential role of different methods for inducing trained immune AMs in the treatment of tuberculosis, including existing bacille Calmette-Guérin (BCG) vaccination and emerging strategies such as lipopolysaccharide (LPS)-mediated Toll-like receptor 4 (TLR4) activation and Influenza A virus (IAV)-induced host trained immunity activation, providing new ideas for the treatment of tuberculosis.

Keywords:  Alveolar macrophages; Antibacterial; Mycobacterium tuberculosis; Trained immunity

DOI:  https://doi.org/10.1016/j.intimp.2025.115211
Front Immunol. 2025 ;16 1609763

Retinoic acid differently modulates NOD1/NOD2-mediated inflammatory responses in human macrophage subsets.

Hala Ahmad, Ahmad Alatshan, Eduárd Bíró, Szilvia Benkő.

  Macrophages are indispensable in homeostasis and innate immune responses in multiple tissues, while their polarization and functional characteristics are determined by the activating stimuli and their tissue microenvironment. The vitamin A derivative retinoic acid shows inhomogeneous distribution among the tissues and has an important modulatory role in inflammatory responses. However, its effects on the cytokine secretion induced by the cytosolic pattern-recognition receptors NOD1 and NOD2 are unclear. In our study, we used human monocyte-derived macrophages differentiated in the presence of GM-CSF or M-CSF to generate inflammation inducing (GM-MФ) or inflammation resolving (M-MФ) cells, respectively. We activated the cells with either a NOD1- or NOD2 specific agonist and, using ELISA, we determined the pattern and dynamics of cytokines secreted by the macrophage subpopulations. Furthermore, we studied the effect of all-trans retinoic acid (ATRA) pre-treatment on the NOD1- and NOD2-induced cytokine release. Our comparative analysis shows subpopulation-characteristic pattern of cytokine secretion, as GM-MФ produce significantly higher pro-inflammatory IL-6, IL-8, TNF-α and IL-1β, while M-MФ secret higher anti-inflammatory IL-10. However, IL-18 and IFNβ secretion was comparable between the MФ subpopulations. We also show for the first time that ATRA has marked impact on cytokine secretion triggered by NOD1 and NOD2. Importantly however, the ATRA-induced changes of cytokine secretion follow opposite tendency in two MФ subpopulations. In conclusion, these results show that NOD1/NOD2-induced cytokine secretion by macrophage subsets is highly context-dependent and our results highlight the importance of the retinoic acid content of the local tissue environment in shaping macrophage function in health and disease.

Keywords:  NOD-like receptor; NOD1; NOD2; cytokine; inflammation; macrophage; retinoic acid; vitamin A

DOI:  https://doi.org/10.3389/fimmu.2025.1609763
bioRxiv. 2025 May 09. pii: 2025.05.06.652565. [Epub ahead of print]

Lantibiotic-producing bacteria impact microbiome resilience and colonization resistance.

Cody G Cole, Zhenrun J Zhang, Shravan R Dommaraju, Qiwen Dong, Rosemary L Pope, Sophie S Son, Emma J McSpadden, Che K Woodson, Huaiying Lin, Nicholas P Dylla, Ashley M Sidebottom, Anitha Sundararajan, Douglas A Mitchell, Eric G Pamer.

A subset of commensal bacterial strains secrete bacteriocins, such as lantibiotics, to establish and protect their niche in the gut. Because the antimicrobial spectrum of lantibiotics includes opportunistic pathogens, such as vancomycin-resistant Enterococcus faecium (VRE), they may provide an approach to reduce antibiotic-resistant infections. The impact of lantibiotic-producing bacteria on the complex microbial populations constituting the microbiome, however, remains poorly defined. We find that genes encoding lanthipeptides, including lantibiotics, are commonly present in the microbiomes of healthy humans and in dysbiotic microbiomes of hospitalized patients. In fecal samples collected from hospitalized patients, bacterial species encoding lantibiotic genes are present in greater abundance than lantibiotic-deficient strains of the same species. We demonstrate that the lantibiotic-producing bacterium, Blautia pseudococcoides SCSK, prevents intestinal recolonization of mice by a wide range of commensal species following antibiotic-induced dysbiosis and markedly reduces fecal concentrations of microbiota-derived metabolites associated with mucosal immune defenses. Lantibiotic-mediated dysbiosis results in sustained loss of colonization resistance against Klebsiella pneumoniae and Clostrioides difficile infection. Our findings reveal the potential impact of lantibiotic-producing bacterial species on microbiome resilience and susceptibility to infection following antibiotic treatment.

DOI: https://doi.org/10.1101/2025.05.06.652565
Gut Microbes. 2025 Dec;17(1): 2527857

SLAMF7 regulates goblet cell mucus production and negatively impacts gut homeostasis and commensalism.

Dianrong Zhou, Changbu Wu, Chengjuan Li, Meisong Li, Zeyu Li, Jiachen Li, Yihao Zhang, Hui Zhao, Yaxuan Wang, Lujie Liang, Lin Xu, Yaxin Li, Lan-Lan Zhong, Siyuan Feng, Guo-Bao Tian.

  Crosstalk between the intestinal mucosal barrier and the gut microbiota contributes to maintaining intestinal homeostasis. Accumulating evidence suggests that diverse mechanisms are involved in maintaining intestinal homeostasis. Any disturbance in these pathways can compromise gut homeostasis and trigger chronic inflammatory diseases such as inflammatory bowel disease (IBD). However, how host factors regulate the intestinal mucosal barrier and change the gut microbiome has not been well defined. Here, we discovered that disruption of SLAMF7 protects against intestinal inflammation. SLAMF7 deficiency significantly altered the intestinal microbiota composition, specifically the expansion of the mucus-specific bacterium Akkermansia muciniphila. Moreover, SLAMF7 deficiency resulted in goblet cell generation by increasing the number of M2-like C1q+ macrophages, which may contribute to a thicker mucosal barrier. Mechanistically, SLAMF7 deficiency increased goblet cell generation through C1q+ M2-like macrophage polarization, which partly led to a thicker mucosal barrier. Depletion of SLAMF7 in intestinal macrophages upregulated C1q via activation of the STAT6-MafB pathway. The upregulation of C1q in macrophages resulted in a bias toward the M2 phenotype in response to damage-associated molecular patterns (DAMPs) stimulation. Accordingly, SLAMF7 activation induced a shift in macrophage polarization and reduced mucus secretion, which partially aggravated intestinal inflammation. Conversely, SLAMF7 knockdown mitigated DSS-induced intestinal inflammation to some extent. This work reveals the previously unrecognized functions of SLAMF7 in regulating intestinal inflammation and tissue homeostasis.

Keywords:  C1Q; Inflammatory bowel disease; SLAMF7; macrophage polarization; microbiota; mucosal barrier

DOI:  https://doi.org/10.1080/19490976.2025.2527857
Metabolism. 2025 Jul 09. pii: S0026-0495(25)00218-5. [Epub ahead of print]171 156349

Metabolic regulation of tissue-resident immune cells: Molecular mechanisms and therapeutic implications.

Zixiang Chen, Fan Xiao, Xiaoxia Zhu, Wenhao Zhou, Ke Rui, Liwei Lu, Jie Tian.

  Many innate and adaptive immune cells are resident in non-lymphoid tissues and do not participate in peripheral circulation. These tissue-resident immune cells not only rapidly recognize and respond to local infections or injuries but also contribute to the maintenance of tissue homeostasis and immune balance. Immune cell function is closely associated with their metabolic state. Recent studies reveal that tissue-resident immune cells undergo unique metabolic reprogramming to adapt to their specific tissue microenvironment. This metabolic adaptation is crucial for their long-term survival, differentiation, and function. In this review, we systematically elaborate on the metabolic characteristics and tissue-specific regulatory mechanisms of CD8+ tissue-resident memory T cells (TRM) and tissue-resident macrophages (TRMφs). Based on an in-depth analysis of the critical role of immunometabolic pathways in infection, cancer, and autoimmune diseases, we further summarize therapeutic strategies targeting these metabolic pathways and discuss their efficacy, potential side effects, and the challenges facing clinical translation.

Keywords:  Metabolism; Targeting therapy; Tissue-resident immune cell; Tissue-resident macrophage; Tissue-resident memory CD8(+) T cell

DOI:  https://doi.org/10.1016/j.metabol.2025.156349
Semin Immunopathol. 2025 Jul 18. 47(1): 30

Macrophage clock of pregnancy: circadian and metabolic control of decidual macrophage.

Dongyong Yang, Kristin Thiele, Tailang Yin, Lianghui Diao.

  The temporal regulation of immune responses during pregnancy is crucial for successful gestation. Yet, the specific mechanisms controlling macrophage function across gestational stages remain poorly understood. Here, we introduce the concept of the "macrophage clock of pregnancy", describing how molecular clock and cellular metabolism coordinate macrophage function across gestational stages. The molecular mechanisms underlying circadian control of macrophage function are examined, as well as hormones secreted by the pineal gland and their relevance to pregnancy-related processes. These pathways orchestrate key macrophage functions in pregnancy: modifying the uterine epithelium during implantation, supporting spiral artery remodeling, maintaining fetal tolerance, and initiating labor. Recent evidence shows that environmental factors such as shift work and extension of artificial light exposure can disturb macrophage function. The temporal regulation of macrophages also depends on metabolic signals, with distinct patterns of glycolysis, oxidative phosphorylation, and fatty acid metabolism corresponding to different gestational phases. Disruption of these temporal and metabolic signals - whether through circadian misalignment or metabolic dysfunction - correlates with pregnancy complications including recurrent pregnancy loss, preeclampsia, and preterm birth. We propose that monitoring macrophage temporal dynamics could provide early indicators of pregnancy complications, while targeting clock-controlled pathways may offer new therapeutic strategies. Understanding the temporal aspects of macrophage function opens new approaches for treating pregnancy disorders through precise immunological timing.

Keywords:  Circadian rhythms; Decidual macrophage; Maternal-fetal interface; Metabolic dysfunction; Molecular clock; Pregnancy complications

DOI:  https://doi.org/10.1007/s00281-025-01057-6
J Inflamm Res. 2025 ;18 8945-8959

Macrophages as Multifaceted Orchestrators of Tissue Repair: Bridging Inflammation, Regeneration, and Therapeutic Innovation.

Li Wang, Kai Yang, Xinxin Xie, Shaohui Wang, Huiping Gan, Xiaoli Wang, Hailiang Wei.

  Macrophages play pivotal roles in tissue repair through remarkable functional plasticity, orchestrated by their developmental origins and local microenvironmental cues. Embryonically derived resident macrophages primarily maintain tissue homeostasis, while monocyte-derived macrophages respond predominantly to inflammation and extracellular matrix remodeling. Effective tissue repair requires precise temporal regulation of macrophage polarization, balancing inflammation resolution, angiogenesis, and scar formation. Metabolic reprogramming further enhances macrophage plasticity, enabling adaptation to fluctuating energy demands at injury sites. Emerging evidence also highlights that macrophages integrate biomechanical forces-such as matrix stiffness and shear stress-with biochemical signals to fine-tune their inflammatory and reparative programs. Recognizing this mechanoregulation broadens therapeutic avenues for precisely modulating macrophage behavior in regenerative medicine. Targeting macrophage subsets, polarization states, or metabolic pathways has emerged as a promising therapeutic strategy to optimize healing outcomes. However, the inherent complexity of macrophage heterogeneity presents considerable challenges to therapeutic precision. This review systematically summarizes the multifaceted roles of macrophages in tissue repair, emphasizing how developmental origins dictate functional specificity, dynamic phenotypic transitions, and metabolic adaptability, aiming to advance macrophage-based precision therapeutics for regenerative medicine.

Keywords:  macrophage; macrophage polarization; therapeutic strategy; tissue repair

DOI:  https://doi.org/10.2147/JIR.S527764
bioRxiv. 2025 Jul 07. pii: 2025.07.02.662833. [Epub ahead of print]

Respiratory syncytial virus infection confers heterologous protection against SARS-CoV-2 via induction of γδ T cell-mediated trained immunity and SARS-CoV-2 reactive mucosal T cells.

Awadalkareem Adam, Wenzhe Wu, Madison C Jones, Haiping Hao, Aditi, Parimal Samir, Xiaoyong Bao, Tian Wang.

The respiratory viruses can concurrently or sequentially infect a host and influence the trajectory of each other. The underlying immune mechanisms are not well understood. Here, we investigated whether respiratory syncytial virus (RSV) infection affects host vulnerability to subsequent SARS-CoV-2 infection in two murine models of SARS-CoV-2 infection. We found that prior RSV infection-induced heterologous protection against subsequent SARS-CoV-2 infection was dose and time dependent. RNA-seq and immunological analyses revealed that RSV triggered the activation of lung antigen presenting cells (APC)s and SARS-CoV-2 reactive mucosal T cells at day 9, which declined at 1 month. RSV also induced the expansion of lung γδ T cells and the upregulation of their cellular metabolic pathways. Furthermore, RSV infection in TCRδ -/- mice, which are deficient of γδ T cells, resulted in a reduced SARS-CoV-2 reactive mucosal T cell response and subsequent increased viral loads and higher levels of virus-induced inflammatory responses in the lung upon SARS-CoV-2 challenge compared to the wild-type mice. In summary, our findings suggest that RSV infection provides heterologous protection against the subsequent SARS-CoV-2 infection via induction of γδ T cell-mediated trained immunity in the lung and SARS-CoV-2 reactive mucosal T cell responses.

DOI: https://doi.org/10.1101/2025.07.02.662833
iScience. 2025 Jul 18. 28(7): 112894

Deep metabolic profiling of immune cells by spectral flow cytometry-A comprehensive validation approach.

Claire L Wishart, Alanna G Spiteri, Jian Tan, Claudio Counoupas, James A Triccas, Laurence Macia, Nicholas J C King.

  The advancing field of immunometabolism requires tools that link single-cell metabolism with immune function. Metabolic flow cytometry provides this capability, but its broad adoption has been limited by costly custom reagents and a lack of standardized methods for validating metabolic targets. Here, we present a standardized and user-friendly spectral flow cytometry panel that profiles eight key metabolic pathways at single-cell resolution using only commercially available antibodies, enabling simultaneous analysis of immune phenotype and metabolic activity . Applying this approach to lung myeloid and T cells following intranasal adenoviral CD40L vaccination revealed distinct metabolic phenotypes between resident and infiltrating myeloid cells, as well as functionally divergent metabolic programs in naive, effector, and tissue-resident memory T cells. Additionally, leveraging NAD(P)H autofluorescence allowed label-free detection of glycolysis and expanded the panel's utility. This standardized approach reduces cost and experimental complexity, enabling researchers to elucidate how metabolism drives immune function across broader immunological and clinical contexts.

Keywords:  Biocomputational method; Immune response; Immunological methods; Metabolomics

DOI:  https://doi.org/10.1016/j.isci.2025.112894
Am J Reprod Immunol. 2025 Jul;94(1): e70123

Macrophage Switching in Pregnancy: Regulatory Mechanisms Governing Term Labour and Preterm Birth.

G Ravi Prakash, Ayushi Vaidhya, V Deepthi, Laxmi Singh Rathore, Manjit Panigrahi, C L Madhu, T U Singh, Subhashree Parida.

  Macrophages play a pivotal role in the immune adaptations required for pregnancy, influencing both term and preterm labour (PTL) through their activation and polarisation. These immune cells originate from the yolk sac, foetal liver, and bone marrow, differentiating into diverse subtypes, including pro-inflammatory (M1) and anti-inflammatory (M2) macrophages. The dynamic transition between these states, termed macrophage switching, is crucial for maintaining pregnancy and orchestrating labour. This switch is tightly regulated by hormones, cytokines and immune signals, ensuring a controlled inflammatory response at term whilst preventing pathological inflammation leading to preterm birth. During term labour, macrophages accumulate in the cervix, decidua and myometrium, responding to signals from placental aging, foetal lung maturation and endocrine changes. They secrete pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), matrix metalloproteinases (MMPs) and prostaglandins, promoting uterine contractions and cervical remodelling. The sources of these macrophages include maternal monocytes recruited from circulation and resident decidual macrophages (DMs). In contrast, PTL often arises from dysregulated macrophage activation due to infection, sterile inflammation, or stress signals, triggering an early pro-inflammatory shift. Premature M1 dominance leads to excessive inflammation, extracellular matrix degradation and foetal membrane rupture. Understanding the mechanisms regulating macrophage switching in PTL, including TLR signalling and hormonal modulation, may uncover therapeutic targets and suitable interventions. This review explores the origins, activation, and functional switching of macrophages in term and preterm labor, emphasising their regulatory mechanisms and potential interventions to prevent preterm birth.

Keywords:  m1/m2; macrophage; macrophage switching; pregnancy; preterm labour

DOI:  https://doi.org/10.1111/aji.70123
Front Microbiol. 2025 ;16 1605044

Understanding the probiotic health benefits of Bifidobacterium animalis subsp. lactis, BB-12™.

Fergus W J Collins, Natalia I Vera-Jiménez, Anja Wellejus.

  Probiotics have a longstanding association with human health, yet the mechanisms behind their benefits are often unclear. To understand the mode of action for the efficacy of a probiotic, it is important to take a broad overview of the interactions between the microbe, its environment, and the host. The BB-12 Bifidobacterium animalis subsp. lactis strain is one of the most documented probiotic strains on the market and has been shown to be effective in alleviating symptoms of a low defecation frequency and infant colic, among others. In this review, we examine the wide range of preclinical and clinical data available for the strain, to help elucidate some of its potential mechanisms of action. We describe the defence mechanisms developed by the strain to ensure gastrointestinal survival and transit, as well as the current knowledge on how BB-12 interacts with the host epithelial lining and cells of the immune system and the relationship between the strain and the gut microbiota. Collectively, the well documented clinical efficacies demonstrated by BB-12 are most likely not through one single mechanism, but through the collective direct and indirect effects the strain has on both its environment and the host.

Keywords:  Bifidobacterium; colic; gut health; microbiome; probiotic

DOI:  https://doi.org/10.3389/fmicb.2025.1605044
Int J Mol Sci. 2025 Jul 03. pii: 6403. [Epub ahead of print]26(13):

Short-Term Probiotic Colonization Alters Molecular Dynamics of 3D Oral Biofilms.

Nadeeka S Udawatte, Chun Liu, Reuben Staples, Pingping Han, Purnima S Kumar, Thiruma V Arumugam, Sašo Ivanovski, Chaminda J Seneviratne.

  Three-dimensional (3D) scaffold systems have proven instrumental in advancing our understanding of polymicrobial biofilm dynamics and probiotic interactions within the oral environment. Among oral probiotics, Streptococcus salivarius K12 (Ssk12) has shown considerable promise in modulating microbial homeostasis; however, its long-term therapeutic benefits are contingent upon successful and sustained colonization of the oral mucosa. Despite its clinical relevance, the molecular mechanisms underlying the adhesion, persistence, and integration of Ssk12 into the native oral microbiome/biofilm remain inadequately characterized. In this pilot study, we explored the temporal colonization dynamics of Ssk12 and its impact on the structure and functional profiles of salivary-derived biofilms cultivated on melt-electrowritten poly(ε-caprolactone) (MEW-mPCL) scaffolds, which emulate the native oral niche. Colonization was monitored via fluorescence in situ hybridization (smFISH), confocal microscopy, and RT-qPCR, while shifts in community composition and function were assessed using 16S rRNA sequencing and meta-transcriptomics. A single administration of Ssk12 exhibited transient colonization lasting up to 7 days, with detectable presence diminishing by day 10. This was accompanied by short-term increases in Lactobacillus and Bifidobacterium populations. Functional analyses revealed increased transcriptional signatures linked to oxidative stress resistance and metabolic adaptation. These findings suggest that even short-term probiotic colonization induces significant functional changes, underscoring the need for strategies to enhance probiotic persistence.

Keywords:  3D melt electrowriting (MEW) medical-grade poly(ε-caprolactone) (mPCL); 3D salivary polymicrobial biofilm model; oral microbiome; probiotic colonization; streptococcus salivarius K12 (Ssk12)

DOI:  https://doi.org/10.3390/ijms26136403
Clin Transl Med. 2025 Jul;15(7): e70419

Itaconate suppresses neonatal intestinal inflammation via metabolic reprogramming of M1 macrophage.

Shuchen Huangfu, Chaoting Lan, Sitao Li, Huijuan Wang, Chun Yan, Yuling Yang, Bowen Tian, Yide Mu, Peizhi Zhao, Yan Tian, Yijia Wang, Wei Zhong, Limei Zhong, Yongyan Shi, Yufeng Liu.

   BACKGROUND: Necrotizing enterocolitis (NEC) is a rapidly progressive and severe gastrointestinal disorder in neonates that is marked by an inflammatory cascade initiated by mechanisms that remain incompletely understood, resulting in intestinal necrosis and systemic infections. This study demonstrated that itaconate (ITA) exerts a protective effect in NEC by regulating macrophage reprogramming.
METHODS: Changes in ITA expression were investigated using immunofluorescence staining and liquid chromatography-mass spectrometry, and their effect on immune cell differentiation was verified through single-cell sequencing. In vivo experiments were performed using ACOD1-/- and ACOD1fl/flLysMcre NEC mouse models.
RESULTS: We detected changes in ITA expression in clinical NEC samples and confirmed the effect of these changes on immune cell differentiation. In vivo experiments confirmed the therapeutic role of ITA in regulating macrophage differentiation in NEC, and we further investigated the mechanism by which ITA regulates macrophage metabolic reprogramming. The depletion of ITA in NEC correlates with an increased frequency of pro-inflammatory macrophage polarization, thereby exacerbating intestinal inflammatory injury. Importantly, our in vivo experiments revealed that treatment with 4-octyl itaconate (4OI) significantly mitigated intestinal symptoms associated with NEC in murine models. Mechanistic investigations showed that 4OI effectively suppressed M1 macrophage polarization by rescuing mitochondrial function and upregulating oxidative phosphorylation in macrophages.
CONCLUSIONS: Our results highlight ITA as a metabolic checkpoint of macrophage differentiation in NEC and suggest the therapeutic efficacy of 4OI in NEC.
KEY POINTS: Itaconate alleviates NEC by reprogramming M1 macrophage metabolism ACOD1 deficiency exacerbates NEC severity 4OI maintains intestinal barrier integrity. 4OI rescues NEC by regulating macrophage mitochondrial activity.

Keywords:  itaconate; macrophage; metabolic reprogramming; necrotizing enterocolitis; oxidative phosphorylation

DOI:  https://doi.org/10.1002/ctm2.70419
Front Immunol. 2025 ;16 1589853

Lactate and lactylation: emerging roles in autoimmune diseases and metabolic reprogramming.

Wenjun Liu, Ruhui Yang, Yuxin Zhan, Xuanyu Yang, Haimin Zeng, Bofan Chen, Jiahao Zeng, Tianheng Hu, Jie Hu, Qi Xiao, Yinjin Shao, Xiang Chen.

  Autoimmune diseases are a set of conditions in which the immune system incorrectly identifies and attacks the body's own healthy tissue, severely compromising patient health. While current treatments can somewhat control disease progression, their long-term effectiveness remains limited, necessitating the development of more effective therapeutic approaches. Lactate and lactylation are critical links between metabolic reprogramming and epigenetics. As an emerging epigenetic modification, lactylation induced by lactate is closely associated with the onset of autoimmune diseases. Lactylation can be categorized into histone and nonhistone modifications, both of which play pivotal roles in cellular functions and pathophysiological processes through distinct regulatory mechanisms. Lactylation impacts immune cell function by regulating metabolic reprogramming and signaling pathways. In autoimmune diseases, immune cell metabolic reprogramming controls lactylation levels through metabolic byproducts, and lactylation, in turn, modulates the cellular metabolism by altering the transcription and structure of key enzymes. These interconnected processes collectively drive disease progression. To better understand the role of lactate and lactylation in the pathogenesis of autoimmune diseases, this review synthesizes the effects on specific immune cells, examining their dual effects on immune system function and their particular impacts on two common autoimmune diseases-rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). By combining the established role of lactate in immune metabolic reprogramming with the emerging understanding of the influence of lactate-induced lactylation on epigenetic regulation, this paper explores the relationship between lactylation and the progression of autoimmune diseases. This approach aims to enhance the understanding of the interplay between epigenetics and metabolism in autoimmune disease development, providing new perspectives for future therapeutic strategies. Studies collectively indicate that treatment can be improved through regulating key enzymes involved in lactylation, targeting lactate production pathways, integrating innovative approaches with current therapies, and adopting personalized treatment strategies.

Keywords:  autoimmune diseases; epigenetics; lactate; lactylation; metabolic reprogramming

DOI:  https://doi.org/10.3389/fimmu.2025.1589853
Nat Commun. 2025 Jul 16. 16(1): 6538

Mycobacterium bovis frd operon phase variation hijacks succinate signaling to drive immunometabolic rewiring and pathogenicity.

Yuhui Dong, Xin Ge, Qingbin Guo, Xichao Ou, Chunfa Liu, Yuanzhi Wang, Ziyi Liu, Ruichao Yue, Weixing Fan, Yanlin Zhao, Xiangmei Zhou.

Tuberculosis (TB), caused by Mycobacterium tuberculosis complex (MTBC) pathogens, remains a global health threat. While bacterial genetic adaptations during host infection are poorly understood, phase variation in genomic homopolymeric tracts (HT) may drive pathogenicity evolution. Here, we demonstrate that M. bovis exploits HT insertion mutations in the fumarate reductase-encoding frd operon to subvert host immunometabolism. In macrophages, wild-type M. bovis secretes FRD-catalyzed succinate, stabilizing hypoxia-inducible factor-1α (HIF-1α) to drive glycolytic reprogramming and IL-1β production. This activates IL-1R-dependent Th1 immunity, restraining bacterial replication. Conversely, M. bovis frd HT insertion mutants impair succinate secretion, suppressing HIF-1α/IL-1β signaling and redirecting immunity toward pathogenic Th17 responses that promote neutrophil infiltration and tissue necrosis. Mice infection models reveal that M. bovis frd mutants exhibit enhanced pathogenicity, with higher pulmonary bacterial burdens. IL-1R blockade phenocopies frd HT insertion mutation effects, exacerbating lung pathology. Crucially, conserved frd HT polymorphisms in clinical M. tb isolates suggest shared immune evasion strategies across MTBC pathogens. Our work uncovers the bacterial gene phase variation mechanism of hijacking the succinate/HIF-1α/IL-1β axis to operate host immunity, providing a framework for targeting host metabolic checkpoints in TB therapy.

DOI: https://doi.org/10.1038/s41467-025-61824-9
Int J Mol Sci. 2025 Jul 04. pii: 6458. [Epub ahead of print]26(13):

Fungal β-Glucans Shape Innate Immune Responses in Human Peripheral Blood Mononuclear Cells (PBMCs): An In Vitro Study on PRR Regulation, Cytokine Expression, and Oxidative Balance.

Elżbieta Kozłowska, Justyna Agier, Sylwia Różalska, Magdalena Jurczak, Aleksandra Góralczyk-Bińkowska, Paulina Żelechowska.

  Fungi are ubiquitous organisms that are capable of transient or persistent colonization in humans. Their polymorphic nature and complex host-mycobiome interactions remain incompletely understood. Emerging evidence highlights the role of resident fungi in modulating immune responses and adapting to host changes, which can trigger a shift from commensalism to parasitism, particularly in immunocompromised individuals. This study evaluated the effects of two major β-glucans-zymosan and curdlan-on the expression of pattern recognition receptors (Dectin1, Dectin2, TLR2, TLR4) in human peripheral blood mononuclear cells (PBMCs). It also examined their impact on reactive oxygen species (ROS) production, cytokine/chemokine gene expression, and antioxidant enzyme expression. Both β-glucans significantly increased the mRNA levels of all tested receptors and enhanced ROS generation. Curdlan downregulated key antioxidant enzymes (SOD1, CAT, GPX1), while zymosan markedly upregulated SOD1. These findings demonstrate that the β-glucans zymosan and curdlan have a substantial influence on PBMC reactivity and oxidative stress responses. Further studies are needed to deepen our understanding of host-fungal interactions and their implications in health and disease.

Keywords:  Dectin-1; Dectin-2; Toll-like receptor; antioxidant enzymes; curdlan; reactive oxygen species; zymosan

DOI:  https://doi.org/10.3390/ijms26136458
bioRxiv. 2025 May 06. pii: 2025.05.05.652090. [Epub ahead of print]

Sialylated CD43 is a glyco-immune checkpoint for macrophage phagocytosis.

Jooho Chung, Mounica Vallurupalli, Sarah Noel, Gail Schor, YuhJong Liu, Celeste Nobrega, Jonathan J Perera, Ewa Wrona, Margaret Hu, Yunkang Lin, David W Wu, Maria Saberi, Ilario Scapozza, Aidan Cruickshank, Elliot C Woods, Cun Lan Chuong, Filippo Birocchi, Ashwin V Kammula, Omar I Avila, Mustafa Kocak, John G Doench, Dean Procter, Lindsey Thornton, Andrew M Brunner, Eric Winer, Daniel J DeAngelo, Jacqueline S Garcia, Richard M Stone, Russell W Jenkins, Marcela V Maus, Timothy A Graubert, Kathleen B Yates, Todd R Golub, Robert T Manguso.

Macrophages in the tumor microenvironment exert potent anti-tumorigenic activity through phagocytosis. Yet therapeutics that enhance macrophage phagocytosis have not improved outcomes in clinical trials for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). To systematically identify regulators of phagocytosis, we performed genome-scale CRISPR knockout screens in human leukemia cells co-cultured with human monocyte-derived macrophages. Surprisingly, we found that whereas the classic "don't eat me" signal CD47 inhibited mouse macrophages, it did not inhibit phagocytosis by human macrophages. In contrast, the O-linked glycosylation and sialylation pathways were strong negative regulators of phagocytosis. In AML, the cell surface O-linked glycoprotein CD43 was the major effector of the O-linked glycosylation and sialylation pathways. Genetic deletion or antibody blockade of CD43 enhanced macrophage phagocytosis. This work highlights the importance of using human platforms to identify immune checkpoints, and nominates CD43 as a glyco-immune regulator of human macrophage phagocytosis.

DOI: https://doi.org/10.1101/2025.05.05.652090
Front Pharmacol. 2025 ;16 1614967

Narirutin treatment accelerates the process of diabetic wound repair by regulating phenotype switching of macrophages through affecting metabolic reprogramming.

Liang Liu, Han Wang, Juan Zhou, Jing Lu, Yan Zhang, Haiyan Liu, Li Lu.

   Introduction: Diabetic foot ulcer (DFU) is one of the most common complications of diabetes, with substantial morbidity and mortality. Narirutin (Nar), a bioactive phytochemical derived from citrus peel, has been suggested to possess anti-inflammatory abilities. However, the involvement of Nar in DFU development remains poorly understood.
Methods: The polarization traits of bone marrow derived macrophages (BMDMs) with indicated treatments were determined by flow cytometry, immunofluorescence staining, western blot and qRT-PCR. Levels of lactate and α-ketoglutarate were measured for investigating the metabolic profiles. The cutaneous wounds of diabetic mice were established for evaluating the promotive roles of Nar in wound healing in vivo.
Results: We found that high glucose treatment significant elevated the contents of TNF-α and IL-1β and lactate and reduced the levels of TGF-β1 and IL-4 and α-ketoglutarate in BMDMs. Then, Nar intervention effectively induced BMDMs repolarization from M1 to M2 state and the molecular mechanism was ascribed to drug-elicited activation of AMPK, which in turn increased the expression of downstream Mfn2, thereby enhancing the activity of oxidative phosphorylation and GATA3 cascade activation and disrupting the progress of glycolysis and NF-κB axis activation. Subsequently, we discovered that Nar injection effectively enhanced the healing rate of skin wounds in diabetic mice. Histological analysis showed that Nar dose-dependently induced dermis growth and collagen deposition in the wound area. Via activating AMPK/Mfn2 axis, Nar inhibited the activity of glycolysis and enhanced the extent of oxidative phosphorylation, accompanied by inflammation repression and angiogenesis promotion in the damaged tissue.
Discussion: Our study discovered that macrophages repolarization to M2 phenotype was required for Nar-induced promotive effects on diabetic wound repair by regulating reprogramming of glucose metabolism via mediating AMPK/Mfn2 pathway, providing a promising strategy for DFU management.

Keywords:  AMPK; diabetic foot ulcer; inflammation; macrophage; metabolic reprogramming; narirutin

DOI:  https://doi.org/10.3389/fphar.2025.1614967
Trends Immunol. 2025 Jul 10. pii: S1471-4906(25)00172-3. [Epub ahead of print]

Border-associated macrophages: guardians of vascular homeostasis.

Rui Xing, Jing Xu.

The border tissues of the brain harbor specialized immune cells known as border-associated macrophages (BAMs), which have vital roles at these interfaces. However, factors governing their development and maintenance remain elusive. In a recent study, Van Hove et al. elegantly demonstrated that interleukin (IL)-34 is critical for sustaining BAMs and enabling their regulation of vascular function.

DOI: https://doi.org/10.1016/j.it.2025.07.005