bims-bac4me 2024-09-29 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2024‒09‒29
thirty-two papers selected by
Chun-Chi Chang, University Hospital Zurich

Innate immunity champions: The diverse functions of macrophages.
Trained immunity-based vaccines for infections and allergic diseases.
Single-cell analysis of human airway epithelium identifies cell type-specific responses to Aspergillus and Coccidioides.
The role of inflammasomes as central inflammatory hubs in Mycobacterium tuberculosis infection.
Complement C3 deposition restricts the proliferation of internalized Staphylococcus aureus by promoting autophagy.
Setting the tone: nociceptors as conductors of immune responses.
A 3D Epithelial-Mesenchymal Co-Culture Model of the Airway Wall Using Native Lung Extracellular Matrix.
Identifying antimicrobials in the human microbiome.
A systematic framework for understanding the microbiome in human health and disease: from basic principles to clinical translation.
Microbial colonization programs are structured by breastfeeding and guide healthy respiratory development.
Impact of HDAC inhibitors on macrophage polarization to enhance innate immunity against infections.
From fat to fire: The lipid-inflammasome connection.
Insights into the multifaceted role of interleukin-37 on human immune cell regulation.
Optimising vaccine immunogenicity in ageing populations: key strategies.
NOX2 mediates NLRP3/ROS facilitating nasal mucosal epithelial inflammation in chronic rhinosinusitis with nasal polyps.
Protocol for lipid mediator profiling and phenotyping of human M1- and M2-monocyte-derived macrophages during host-pathogen interactions.
NOD1 and NOD2: Essential Monitoring Partners in the Innate Immune System.
Bifidobacterium breve DSM 32583 and Limosilactobacillus fermentum CECT5716 postbiotics attenuate S. aureus and IL-33-induced Th2 responses.
Taurochenodeoxycholic acid ameliorates the Staphylococcus aureus infection-induced acute lung injury through toll-like receptor 2 in mice.
Intravenous Bacillus Calmette-Guérin (BCG) Induces a More Potent Airway and Lung Immune Response than Intradermal BCG in Simian Immunodeficiency Virus-infected Macaques.
Mycobacterium manipulate glutaminase 1 mediated glutaminolysis to regulate macrophage autophagy for bacteria intracellular survival.
Pyruvate metabolism dictates fibroblast sensitivity to GLS1 inhibition during fibrogenesis.
Staphylococcus epidermidis augments human β-defensin-3 synthesis through the transforming growth factor alpha-epidermal growth factor receptor cascade.
BACH to the ferroptosis.
Inhibition of FABP4 Ameliorates IL-13-Induced Inflammatory Response and Barrier Dysfunction in Nasal Mucosal Epithelial Cells through the Regulation of Ferroptosis.
(Don't) take my breath away: Rare epithelial cells in our airways initiate reflexes to guard against harmful stimuli.
Topical Probiotic Hydrogels for Burn Wound Healing.
Antimicrobial Resistance: A Global Public Health Concern that Needs Perspective Combating Strategies and New Talented Antibiotics.
Mucosal Trained-Immunity Based Vaccines: Cutting Recurrent Infections in Autoimmune Patients on Immunosuppression.
Inflammatory Modulation Effects of Probiotics: A Safe and Promising Modulator for Cancer Prevention.
Microbial hoolIgAn dismantles gut defenses.
Repeated LPS induces training and tolerance of microglial responses across brain regions.

Eur J Immunol. 2024 Sep 23. e2451139

Innate immunity champions: The diverse functions of macrophages.

Francesca Biscu, Anissa Zouzaf, Donatella Cicia, Clare Pridans, Gianluca Matteoli.

  Macrophages are instrumental in maintaining tissue homeostasis, modulating inflammation, and driving regeneration. The advent of omics techniques has led to the identification of numerous tissue-specific macrophage subtypes, thereby introducing the concept of the "macrophage niche". This paradigm underscores the ability of macrophages to adapt their functions based on environmental cues, such as tissue-specific signals. This adaptability is closely linked to their metabolic states, which are crucial for their function and role in health and disease. Macrophage metabolism is central to their ability to switch between proinflammatory and anti-inflammatory states. In this regard, environmental factors, including the extracellular matrix, cellular interactions, and microbial metabolites, profoundly influence macrophage behavior. Moreover, diet and gut microbiota significantly impact macrophage function, with nutrients and microbial metabolites influencing their activity and contributing to conditions like inflammatory bowel disease. Targeting specific macrophage functions and their metabolic processes is leading to the development of novel treatments for a range of chronic inflammatory conditions. The exploration of macrophage biology enriches our understanding of immune regulation and holds the promise of innovative approaches to managing diseases marked by inflammation and immune dysfunction, offering a frontier for scientific and clinical advancement.

Keywords:  Chronic diseases; Inflammation; Macrophages; Metabolism; Therapies

DOI:  https://doi.org/10.1002/eji.202451139
J Allergy Clin Immunol. 2024 Sep 18. pii: S0091-6749(24)00979-5. [Epub ahead of print]

Trained immunity-based vaccines for infections and allergic diseases.

Leticia Martín-Cruz, Cristina Benito-Villalvilla, Alba Angelina, José Luis Subiza, Oscar Palomares.

  Trained immunity has emerged as a new concept in immunology associated with the memory of innate immune cells and linked to specific metabolic and epigenetic reprogramming of these cells. Trained immunity may confer nonspecific and sustained protection against a broad range of pathogens, and recent findings show that it might also be involved in allergy mechanisms. Some conventional vaccines have demonstrated trained immunity induction as the mechanism underlying their heterologous protection. The development of novel vaccines especially designed for this purpose (trained immunity-based vaccines) might be useful in the absence of conventional vaccines or in specific clinical settings. Under certain circumstances, trained immunity could lead to persistent inflammatory innate immune cell responses in allergic subjects, which could be associated with the development and worsening of allergy by promoting and amplifying aberrant type 2 immune responses. In other cases, trained immunity may help promote healthy immune responses to allergens, such as type 1 responses that counterbalance type 2 inflammation or regulatory T cells that induce tolerance. Trained immunity-based allergen vaccines could become the next generation of allergen-specific immunotherapy vaccines, harnessing the potential of trained immunity to induce allergen tolerance. The identification and characterization of proper training inducers might well pave the way for the development of novel immunotherapies.

Keywords:  Trained Immunity-based Vaccines (TIbV); allergic diseases; infectious diseases; metabolic and epigenetic rewiring; trained tolerance-based vaccines

DOI:  https://doi.org/10.1016/j.jaci.2024.09.009
bioRxiv. 2024 Sep 13. pii: 2024.09.09.612147. [Epub ahead of print]

Single-cell analysis of human airway epithelium identifies cell type-specific responses to Aspergillus and Coccidioides.

Alfred T Harding, Arianne J Crossen, Jennifer L Reedy, Kyle J Basham, Olivia W Hepworth, Yanting Zhang, Viral S Shah, Hannah Brown Harding, Manalee V Surve, Patricia Simaku, Geneva N Kwaku, Kristine Nolling Jensen, Yohana Otto, Rebecca A Ward, George R Thompson, Bruce S Klein, Jayaraj Rajagopal, Pritha Sen, Adam L Haber, Jatin M Vyas.

Respiratory fungal infections pose a significant threat to human health. Animal models do not fully recapitulate human disease, necessitating advanced models to study human-fungal pathogen interactions. In this study, we utilized primary human airway epithelial cells (hAECs) to recapitulate the lung environment in vitro and investigate cellular responses to two diverse, clinically significant fungal pathogens, Aspergillus fumigatus and Coccidioides posadasii . To understand the mechanisms of early pathogenesis for both fungi, we performed single-cell RNA sequencing of infected hAECs. Analysis revealed that both fungi induced cellular stress and cytokine production. However, the cell subtypes affected and specific pathways differed between fungi, with A. fumigatus and C. posadasii triggering protein-folding-related stress in ciliated cells and hypoxia responses in secretory cells, respectively. This study represents one of the first reports of single-cell transcriptional analysis of hAECs infected with either A. fumigatus or C. posadasii , providing a vital dataset to dissect the mechanism of disease and potentially identify targetable pathways.Importance: Fungal infections in the lungs are dreaded complications for those with compromised immune systems and have limited treatment strategies available. These options are restricted further by the increased prevalence of treatment-resistant fungi. Many studies focus on how our immune systems respond to these pathogens, yet airway epithelial cells remain an understudied component of fungal infections in the lungs. Here, the authors provide a transcriptional analysis of primary human airway epithelial cells stimulated by two distinct fungal pathogens, Aspergillus fumigatus and Coccidioides posadasii . These data will enable further mechanistic studies of the contribution of the airway epithelium to initial host responses and represent a powerful new resource for investigators.

DOI: https://doi.org/10.1101/2024.09.09.612147
Front Immunol. 2024 ;15 1436676

The role of inflammasomes as central inflammatory hubs in Mycobacterium tuberculosis infection.

Sebastian J Theobald, Tony A Müller, Dinah Lange, Katharina Keck, Jan Rybniker.

  Mycobacterium tuberculosis (Mtb) infection represents a global health problem and is characterized by formation of granuloma with a necrotic center and a systemic inflammatory response. Inflammasomes have a crucial role in the host immune response towards Mtb. These intracellular multi-protein complexes are assembled in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Inflammasome platforms activate caspases, leading to the maturation of the proinflammatory cytokines interleukin (IL)-1 and 18 and the cleavage of gasdermin D (GSDMD), a pore-forming protein responsible for cytokine release and pyroptotic cell death. Recent in vitro and in vivo findings have highlighted the importance of inflammasome signaling and subsequent necrotic cell death in Mtb-infected innate immune cells. However, we are just beginning to understand how inflammasomes contribute to disease or to a protective immune response in tuberculosis (TB). A detailed molecular understanding of inflammasome-associated pathomechanisms may foster the development of novel host-directed therapeutics or vaccines with improved activity. In this mini-review, we discuss the regulatory and molecular aspects of inflammasome activation and the associated immunological consequences for Mtb pathogenesis.

Keywords:  AIM2 inflammasome; Mycobacterium tuberculosis; NLRP3 inflammasome; drug resistance; gasdermin; inflammasome; interleukin-1; tuberculosis

DOI:  https://doi.org/10.3389/fimmu.2024.1436676
Front Cell Infect Microbiol. 2024 ;14 1400068

Complement C3 deposition restricts the proliferation of internalized Staphylococcus aureus by promoting autophagy.

Yining Deng, Yunke Zhang, Tong Wu, Kang Niu, Xiaoyu Jiao, Wenge Ma, Chen Peng, Wenxue Wu.

  Complement C3 (C3) is usually deposited spontaneously on the surfaces of invading bacteria prior to internalization, but the impact of C3 coating on cellular responses is largely unknown. Staphylococcus aureus (S. aureus) is a facultative intracellular pathogen that subverts autophagy and replicates in both phagocytic and nonphagocytic cells. In the present study, we deposited C3 components on the surface of S. aureus by complement opsonization before cell infection and confirmed that C3-coatings remained on the surface of the bacteria after they have invaded the cells, suggesting S. aureus cannot escape or degrade C3 labeling. We found that the C3 deposition on S. aureus notably enhanced cellular autophagic responses, and distinguished these responses as xenophagy, in contrast to LC3-associated phagocytosis (LAP). Furthermore, this upregulation was due to the recruitment of and direct interaction with autophagy-related 16-like 1 (ATG16L1), thereby resulting in autophagy-dependent resistance to bacterial growth within cells. Interestingly, this autophagic effect occurred only after C3 activation by enzymatic cleavage because full-length C3 without cleavage of the complement cascade reaction, although capable of binding to ATG16L1, failed to promote autophagy. These findings demonstrate the biological function of intracellular C3 upon bacterial infection in enhancing autophagy against internalized S. aureus.

Keywords:  ATG16L1; Staphylococcus aureus; autophagy; complement C3; intracellular proliferation

DOI:  https://doi.org/10.3389/fcimb.2024.1400068
Trends Immunol. 2024 Sep 21. pii: S1471-4906(24)00193-5. [Epub ahead of print]

Setting the tone: nociceptors as conductors of immune responses.

Pavel Hanč, Marie-Angèle Messou, Jainu Ajit, Ulrich H von Andrian.

  Nociceptors have emerged as master regulators of immune responses in both homeostatic and pathologic settings; however, their seemingly contradictory effects on the functions of different immune cell subsets have been a source of confusion. Nevertheless, work by many groups in recent years has begun to identify patterns of the modalities and consequences of nociceptor-immune system communication. Here, we review recent findings of how nociceptors affect immunity and propose an integrated concept whereby nociceptors are neither inherently pro- nor anti-inflammatory. Rather, we propose that nociceptors have the role of a rheostat that, in a context-dependent manner, favors tissue homeostasis and fine-tunes immunity by preventing excessive histotoxic inflammation, promoting tissue repair, and potentiating anticipatory and adaptive immune responses.

Keywords:  inflammation; neuroimmunology; nociceptors; tissue homeostasis

DOI:  https://doi.org/10.1016/j.it.2024.08.007
Bioengineering (Basel). 2024 Sep 21. pii: 946. [Epub ahead of print]11(9):

A 3D Epithelial-Mesenchymal Co-Culture Model of the Airway Wall Using Native Lung Extracellular Matrix.

Roderick H J de Hilster, Marjan A Reinders-Luinge, Annemarie Schuil, Theo Borghuis, Martin C Harmsen, Janette K Burgess, Machteld N Hylkema.

  Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by ongoing inflammation, impaired tissue repair, and aberrant interplay between airway epithelium and fibroblasts, resulting in an altered extracellular matrix (ECM) composition. The ECM is the three-dimensional (3D) scaffold that provides mechanical support and biochemical signals to cells, now recognized not only as a consequence but as a potential driver of disease progression. To elucidate how the ECM influences pathophysiological changes occurring in COPD, in vitro models are needed that incorporate the ECM. ECM hydrogels are a novel experimental tool for incorporating the ECM in experimental setups. We developed an airway wall model by combining lung-derived ECM hydrogels with a co-culture of primary human fibroblasts and epithelial cells at an air-liquid interface. Collagen IV and a mixture of collagen I, fibronectin, and bovine serum albumin were used as basement membrane-mimicking coatings. The model was initially assembled using porcine lung-derived ECM hydrogels and subsequently with COPD and non-COPD human lung-derived ECM hydrogels. The resulting 3D construct exhibited considerable contraction and supported co-culture, resulting in a differentiated epithelial layer. This multi-component 3D model allows the investigation of remodelling mechanisms, exploring ECM involvement in cellular crosstalk, and holds promise as a model for drug discovery studies exploring ECM involvement in cellular interactions.

Keywords:  COPD; TWOMBLI; extracellular matrix

DOI:  https://doi.org/10.3390/bioengineering11090946
Nat Rev Drug Discov. 2024 Sep 27.

Identifying antimicrobials in the human microbiome.

Sarah Crunkhorn.

DOI: https://doi.org/10.1038/d41573-024-00157-6
Signal Transduct Target Ther. 2024 Sep 23. 9(1): 237

A systematic framework for understanding the microbiome in human health and disease: from basic principles to clinical translation.

Ziqi Ma, Tao Zuo, Norbert Frey, Ashraf Yusuf Rangrez.

The human microbiome is a complex and dynamic system that plays important roles in human health and disease. However, there remain limitations and theoretical gaps in our current understanding of the intricate relationship between microbes and humans. In this narrative review, we integrate the knowledge and insights from various fields, including anatomy, physiology, immunology, histology, genetics, and evolution, to propose a systematic framework. It introduces key concepts such as the 'innate and adaptive genomes', which enhance genetic and evolutionary comprehension of the human genome. The 'germ-free syndrome' challenges the traditional 'microbes as pathogens' view, advocating for the necessity of microbes for health. The 'slave tissue' concept underscores the symbiotic intricacies between human tissues and their microbial counterparts, highlighting the dynamic health implications of microbial interactions. 'Acquired microbial immunity' positions the microbiome as an adjunct to human immune systems, providing a rationale for probiotic therapies and prudent antibiotic use. The 'homeostatic reprogramming hypothesis' integrates the microbiome into the internal environment theory, potentially explaining the change in homeostatic indicators post-industrialization. The 'cell-microbe co-ecology model' elucidates the symbiotic regulation affecting cellular balance, while the 'meta-host model' broadens the host definition to include symbiotic microbes. The 'health-illness conversion model' encapsulates the innate and adaptive genomes' interplay and dysbiosis patterns. The aim here is to provide a more focused and coherent understanding of microbiome and highlight future research avenues that could lead to a more effective and efficient healthcare system.

DOI: https://doi.org/10.1038/s41392-024-01946-6
Cell. 2024 Sep 19. pii: S0092-8674(24)00782-7. [Epub ahead of print]187(19): 5431-5452.e20

Microbial colonization programs are structured by breastfeeding and guide healthy respiratory development.

Liat Shenhav, Kelsey Fehr, Myrtha E Reyna, Charisse Petersen, Darlene L Y Dai, Ruixue Dai, Vanessa Breton, Laura Rossi, Marek Smieja, Elinor Simons, Michael A Silverman, Maayan Levy, Lars Bode, Catherine J Field, Jean S Marshall, Theo J Moraes, Piush J Mandhane, Stuart E Turvey, Padmaja Subbarao, Michael G Surette, Meghan B Azad.

  Breastfeeding and microbial colonization during infancy occur within a critical time window for development, and both are thought to influence the risk of respiratory illness. However, the mechanisms underlying the protective effects of breastfeeding and the regulation of microbial colonization are poorly understood. Here, we profiled the nasal and gut microbiomes, breastfeeding characteristics, and maternal milk composition of 2,227 children from the CHILD Cohort Study. We identified robust colonization patterns that, together with milk components, predict preschool asthma and mediate the protective effects of breastfeeding. We found that early cessation of breastfeeding (before 3 months) leads to the premature acquisition of microbial species and functions, including Ruminococcus gnavus and tryptophan biosynthesis, which were previously linked to immune modulation and asthma. Conversely, longer exclusive breastfeeding supports a paced microbial development, protecting against asthma. These findings underscore the importance of extended breastfeeding for respiratory health and highlight potential microbial targets for intervention.

Keywords:  asthma; breastfeeding; computational biology; development; early life; gut microbiome; human milk; machine learning; microbial dynamics; microbiome development; nasal microbiome; respiratory health

DOI:  https://doi.org/10.1016/j.cell.2024.07.022
Drug Discov Today. 2024 Sep 25. pii: S1359-6446(24)00318-0. [Epub ahead of print] 104193

Impact of HDAC inhibitors on macrophage polarization to enhance innate immunity against infections.

Mohammad Faizan Bhat, Sonja Srdanović, Lotta-Riina Sundberg, Helga Kristín Einarsdóttir, Varpu Marjomäki, Frank J Dekker.

  Innate immunity plays an important role in host defense against pathogenic infections. It involves macrophage polarization into either the pro-inflammatory M1 or the anti-inflammatory M2 phenotype, influencing immune stimulation or suppression, respectively. Epigenetic changes during immune reactions contribute to long-term innate immunity imprinting on macrophage polarization. It is becoming increasingly evident that epigenetic modulators, such as histone deacetylase (HDAC) inhibitors (HDACi), enable the enhancement of innate immunity by tailoring macrophage polarization in response to immune stressors. In this review, we summarize current literature on the impact of HDACi and other epigenetic modulators on the functioning of macrophages during diseases that have a strong immune component, such as infections. Depending on the disease context and the chosen therapeutic intervention, HDAC1, HDAC2, HDAC3, HDAC6, or HDAC8 are particularly important in influencing macrophage polarization towards either M1 or M2 phenotypes. We anticipate that therapeutic strategies based on HDAC epigenetic mechanisms will provide a unique approach to boost immunity against disease challenges, including resistant infections.

Keywords:  HDAC; infections; inflammation; innate immunity; macrophage polarization

DOI:  https://doi.org/10.1016/j.drudis.2024.104193
Immunol Rev. 2024 Sep 27.

From fat to fire: The lipid-inflammasome connection.

Paras K Anand.

  Inflammasomes are multiprotein complexes that play a crucial role in regulating immune responses by governing the activation of Caspase-1, the secretion of pro-inflammatory cytokines, and the induction of inflammatory cell death, pyroptosis. The inflammasomes are pivotal in effective host defense against a range of pathogens. Yet, overt activation of inflammasome signaling can be detrimental. The most well-studied NLRP3 inflammasome has the ability to detect a variety of stimuli including pathogen-associated molecular patterns, environmental irritants, and endogenous stimuli released from dying cells. Additionally, NLRP3 acts as a key sensor of cellular homeostasis and can be activated by disturbances in diverse metabolic pathways. Consequently, NLRP3 is considered a key player linking metabolic dysregulation to numerous inflammatory disorders such as gout, diabetes, and atherosclerosis. Recently, compelling studies have highlighted a connection between lipids and the regulation of NLRP3 inflammasome. Lipids are integral to cellular processes that serve not only in maintaining the structural integrity and subcellular compartmentalization, but also in contributing to physiological equilibrium. Certain lipid species are known to define NLRP3 subcellular localization, therefore directly influencing the site of inflammasome assembly and activation. For instance, phosphatidylinositol 4-phosphate plays a crucial role in NLRP3 localization to the trans Golgi network. Moreover, new evidence has demonstrated the roles of lipid biosynthesis and trafficking in activation of the NLRP3 inflammasome. This review summarizes and discusses these emerging and varied roles of lipid metabolism in inflammasome activation. A deeper understanding of lipid-inflammasome interactions may open new avenues for therapeutic interventions to prevent or treat chronic inflammatory and autoimmune conditions.

Keywords:  FASN; NLRP3; cholesterol; cholesterol trafficking; fatty acid biosynthesis; inflammasomes; lipid metabolism; lipids; phosphatidylinositol

DOI:  https://doi.org/10.1111/imr.13403
Clin Immunol. 2024 Sep 20. pii: S1521-6616(24)00477-7. [Epub ahead of print]268 110368

Insights into the multifaceted role of interleukin-37 on human immune cell regulation.

Lisa U Teufel, Vasiliki Matzaraki, Lukas Folkman, Rob Ter Horst, Simone J C F M Moorlag, Catharina M Mulders-Manders, Mihai G Netea, Thomas Krausgruber, Leo A B Joosten, Rob J W Arts.

  Autoinflammatory diseases, while having a variety of underlying causes, are mediated by dysfunctional innate immune responses. Therefore, standard treatments target innate cytokines or block their receptors. Despite excellent responses in some patients, first-line treatments fail in others, for reasons which remain to be understood. We studied the effects of IL-37, an anti-inflammatory cytokine, on immune cells using multi-omics profiling of 325 healthy adults. Our findings show that IL-37 is associated with inflammation control and generally reduced immune cell activity. Further, genetic variants in IL37 are associated with impaired trained immunity, a memory phenotype of innate immune cells contributing to autoinflammation. To underpin the medical potential of IL-37, an explorative cohort of seven autoinflammatory disorders was built. In vitro stimulation experiments argue for recombinant IL-37 as a potential therapy in IL-6-, and IL-22-driven conditions. Concluding, IL-37 is highlighted as a cytokine with broad anti-inflammatory functions, implicating its potential as therapeutic intervention.

Keywords:  Autoinflammation; BCG; Inflammation; Interleukin (IL)-37; Trained immunity

DOI:  https://doi.org/10.1016/j.clim.2024.110368
Lancet Infect Dis. 2024 Sep 23. pii: S1473-3099(24)00497-3. [Epub ahead of print]

Optimising vaccine immunogenicity in ageing populations: key strategies.

Guangzhen Jiang, Yushu Zou, Dongyu Zhao, Jingyou Yu.

Vaccination has been shown to be the most effective means of preventing infectious diseases, although older people commonly have a suboptimal immune response to vaccines and thus impaired protection against subsequent adverse outcomes. This Review provides an overview of the existing mechanistic insights into compromised vaccine response for respiratory infectious diseases in older people, defined as aged 65 years and older, including immunosenescence, epigenetic regulation, trained immunity, and gut microbiota. We further summarise the latest proven or potential strategies to strengthen weakened immunogenicity. Insights from these analyses will be conducive to the development of the next generation of vaccines.

DOI: https://doi.org/10.1016/S1473-3099(24)00497-3
Heliyon. 2024 Sep 30. 10(18): e38029

NOX2 mediates NLRP3/ROS facilitating nasal mucosal epithelial inflammation in chronic rhinosinusitis with nasal polyps.

Sijie Jiang, Benjian Zhang, Sihui Wen, Shenghao Cheng, Yingchun Shen, Shaobing Xie, Zhihai Xie, Weihong Jiang.

  Background: Previous investigations have provided limited insight into the role of oxidative stress in nasal mucosa inflammation. The aim of this study was to investigate the mechanism of oxidative stress in the epithelial cells of chronic rhinosinusitis with nasal polyps CRSwNP utilizing single-cell RNA sequencing data.Methods: Single-cell RNA sequencing data from HRA000772 were used to assess oxidative stress, inflammasome activation, and nicotinamide adenine dinucleotide phosphate oxidases (NOXs) expression in epithelial cells via integrative rank-based gene set enrichment analysis. The localization of reactive oxygen species (ROS) and NOX2 in nasal mucosa and cell models was visualized using fluorescent probes and immunohistochemistry, respectively. Functional studies on NOX2 involved siRNA and plasmid transfections in vitro, while Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activity was examined using the inducer TMAO and the inhibitor MCC950.
Results: Single-cell RNA sequencing data suggested an increase of oxidative stress score and NLRP3 inflammasome score in CRSwNP epithelial cells. Vitro experiments demonstrated that lipopolysaccharide could induce ROS accumulation, NLRP3 inflammasome activation and epithelial alarmin expression. MCC950 inhibited the expression of epithelia alarmin in vitro. Elevated NOX2 in CRSwNP epithelial cells was associated with increased ROS, NLRP3 inflammasome activation, and epithelial alarmin expression. NOX2-targeted siRNA inhibited these effects in vitro. Moreover, TMAO reversed the downregulation of epithelial alarmins without impacting ROS levels.
Conclusion: This study highlights the crucial role of NOX2 as a key regulator of ROS accumulation and NLRP3 inflammasome activation in CRSwNP, underscoring its potential as a valuable therapeutic target for CRSwNP.

Keywords:  Chronic rhinosinusitis with nasal polyps; NADPH oxidase 2; Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3; Oxidative stress; Single-cell RNA-Sequencing

DOI:  https://doi.org/10.1016/j.heliyon.2024.e38029
STAR Protoc. 2024 09 20. pii: S2666-1667(24)00307-1. [Epub ahead of print]5(3): 103142

Protocol for lipid mediator profiling and phenotyping of human M1- and M2-monocyte-derived macrophages during host-pathogen interactions.

Kerstin Günther, Christina Ehrhardt, Oliver Werz, Paul M Jordan.

  Here, we present a protocol for primary, human immune cell isolation and stimulation for lipid mediator profiling. We describe steps for the isolation of monocytes from human leukocyte concentrates via density centrifugation and differentiation/polarization toward M1- or M2-monocyte-derived macrophages (MDMs). We detail stimulation approaches of MDMs with live bacteria or influenza A virus for lipid mediator profiling and sample preparation for subsequent analysis, such as enzyme expression, mRNA analysis, or surface marker determination. For complete details on the use and execution of this protocol, please refer to Jordan et al.1.

Keywords:  Cell Biology; Cell isolation; Cell-based Assays; Immunology; Microbiology

DOI:  https://doi.org/10.1016/j.xpro.2024.103142
Curr Issues Mol Biol. 2024 Aug 28. 46(9): 9463-9479

NOD1 and NOD2: Essential Monitoring Partners in the Innate Immune System.

Zhenjia Li, Dejing Shang.

  Nucleotide-binding oligomerization domain containing 1 (NOD1) and NOD2 are pivotal cytoplasmic pattern-recognition receptors (PRRs) that exhibit remarkable evolutionary conservation. They possess the ability to discern specific peptidoglycan (PGN) motifs, thereby orchestrating innate immunity and contributing significantly to immune homeostasis maintenance. The comprehensive understanding of both the structure and function of NOD1 and NOD2 has been extensively elucidated. These receptors proficiently recognize an array of damage-associated molecular patterns (DAMPs) as well as pathogen-associated molecular patterns (PAMPs), subsequently mediating inflammatory responses and autophagy. In recent years, emerging evidence has highlighted the crucial roles played by NOD1 and NOD2 in regulating infectious diseases, metabolic disorders, cancer, and autoimmune conditions, among others. Perturbation in either their loss or excessive activation can detrimentally impact immune homeostasis. This review offers a comprehensive overview of the structural characteristics, subcellular localization, activation mechanisms, and significant roles of NOD1 and NOD2 in innate immunity and related disease.

Keywords:  NOD1; NOD2; inflammatory response; innate immunity

DOI:  https://doi.org/10.3390/cimb46090561
Microbiol Res. 2024 Sep 21. pii: S0944-5013(24)00314-8. [Epub ahead of print]289 127913

Bifidobacterium breve DSM 32583 and Limosilactobacillus fermentum CECT5716 postbiotics attenuate S. aureus and IL-33-induced Th2 responses.

Yacine Amar, Jana Grube, Martin Köberle, Monika Schaubeck, Tilo Biedermann, Thomas Volz.

  Over the past decades, the prevalence of allergic diseases noticeably increased in industrialized countries. The Th2 immune response plays a central role in these pathologies and its modulation using pro-/postbiotics constitutes a promising approach to prevent or alleviate disease symptoms. The aim of this in vitro study, was to investigate the ability of human milk-derived Bifidobacterium breve DSM 32583 (Bb) and Limosilactobacillus fermentum CECT5716 (Lf), to modulate the Th2 induced responses. To this end, Th2 cells were generated by co-culturing of human naïve Th cells with monocyte-derived dendritic cells (moDCs) either stimulated with Staphylococcus aureus or IL-33. The immunomodulatory effects of pro-/postbiotic preparations of Bb and Lf on moDCs and Th2 cells were evaluated in terms of maturation markers expression and cytokines production. Remarkably, the tested strains induced the anti-inflammatory cytokine IL-10 in moDCs, in a strain-, dose- and viability-dependent manner with no significant upregulation of IL-12p70 nor CD83, CD86 or HLA-DR. Interestingly, Bb and Lf postbiotics were able to dampen the Th2/Th1 response induced upon S. aureus- or IL-33 stimulation. They were also able to synergistically induce IL-10 in moDCs and T cells, upon co-stimulation with LPS. Finally, we observed that live probiotics triggered a mild Th1 response that was attenuated in the presence of galacto-oligosaccharides. Altogether, Bb and Lf pro-/postbiotics exhibited remarkable immune regulatory effects on both moDCs and Th2 cells. Therefore, further in vivo studies should be considered to validate these findings and assess their ability to prevent allergy or alleviate its symptoms in affected patients.

Keywords:  Allergy; Bifidobacterium breve; GOS; IL-33; Limosilactobacillus fermentum; S. aureus

DOI:  https://doi.org/10.1016/j.micres.2024.127913
Int Immunopharmacol. 2024 Sep 23. pii: S1567-5769(24)01750-8. [Epub ahead of print]142(Pt B): 113228

Taurochenodeoxycholic acid ameliorates the Staphylococcus aureus infection-induced acute lung injury through toll-like receptor 2 in mice.

Zhiguo Gong, Wei Mao, Peipei Ren, Zhichao Hao, Jiamin Zhao, Zhuoya Yu, Yi Zhao, Yaya Feng, Bo Liu, Shuangyi Zhang.

  Acute lung injury (ALI) is a significant clinical problem associated with high morbidity and mortality. Inflammation induced by gram-positive bacterial pathogens, specifically Staphylococcus aureus (S. aureus), plays a major role in ALI development and other infectious diseases. Taurochenodeoxycholic acid (TCDCA) exhibits diverse biological activities and pharmacological effects. Nevertheless, the potential preventive and therapeutic effects of TCDCA and the underlying mechanism in the ALI induced by S. aureus infection remain poorly understood. Our results showed that the TCDCA (0.1 μg/g) had a beneficial effect on lung damage in mice infected with S. aureus. Specifically, TCDCA could lead to a reduction in pulmonary focal or diffuse oedema and a decrease in the infiltration of neutrophils in the S. aureus-infected lungs. We observed that TCDCA could significantly down-regulate the expression of HMGB1 in lung from S. aureus-infected mice. Furthermore, TCDCA could attenuate the production of inflammatory mediators in lungs and serum from S. aureus-infected mice. This finding further supported the notion that TCDCA potentially protects against tissue injury. In addition, TCDCA regulated the secretion of the proinflammatory cytokine, the activation of MAPK and NF-κB signaling pathways, and the activation of TLR2 in macrophages. Notably, TCDCA might reduce the secretion levels of inflammatory mediators and lung damage through the TLR2 in S. aureus-infected macrophages or mice. Altogether, TCDCA shows promise as a potential drug for preventing and treating ALI by modulating or inhibiting inflammatory mediators through TLR2.

Keywords:  Acute lung injury; Macrophage; Staphylococcus aureus; Taurochenodeoxycholic acid; Toll-like receptor 2

DOI:  https://doi.org/10.1016/j.intimp.2024.113228
J Immunol. 2024 Sep 23. pii: ji2400417. [Epub ahead of print]

Intravenous Bacillus Calmette-Guérin (BCG) Induces a More Potent Airway and Lung Immune Response than Intradermal BCG in Simian Immunodeficiency Virus-infected Macaques.

Solomon Jauro, Erica C Larson, Janelle L Gleim, Brendon M Wahlberg, Mark A Rodgers, Julia C Chehab, Alondra E Lopez-Velazques, Cassaundra L Ameel, Jaime A Tomko, Jennifer L Sakal, Todd DeMarco, H Jacob Borish, Pauline Maiello, E Lake Potter, Mario Roederer, Philana Ling Lin, JoAnne L Flynn, Charles A Scanga.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the leading causes of death due to an infectious agent. Coinfection with HIV exacerbates M. tuberculosis infection outcomes in people living with HIV. Bacillus Calmette-Guérin (BCG), the only approved TB vaccine, is effective in infants, but its efficacy in adolescents and adults is limited. In this study, we investigated the immune responses elicited by BCG administered via i.v. or intradermal (i.d.) routes in SIV-infected Mauritian cynomolgus macaques (MCM) without the confounding effects of M. tuberculosis challenge. We assessed the impact of vaccination on T cell responses in the airway, blood, and tissues (lung, thoracic lymph nodes, and spleen), as well as the expression of cytokines, cytotoxic effectors, and key transcription factors. Our results showed that i.v. BCG induces a robust and sustained immune response, including tissue-resident memory T cells in lungs, polyfunctional CD4+ and CD8αβ+ T cells expressing multiple cytokines, and CD8αβ+ T cells and NK cells expressing cytotoxic effectors in airways. We also detected higher levels of mycobacteria-specific IgG and IgM in the airways of i.v. BCG-vaccinated MCM. Although i.v. BCG vaccination resulted in an influx of tissue-resident memory T cells in lungs of MCM with controlled SIV replication, MCM with high plasma SIV RNA (>105 copies/ml) typically displayed reduced T cell responses, suggesting that uncontrolled SIV or HIV replication would have a detrimental effect on i.v. BCG-induced protection against M. tuberculosis.

DOI: https://doi.org/10.4049/jimmunol.2400417
Cell Signal. 2024 Sep 20. pii: S0898-6568(24)00390-5. [Epub ahead of print]124 111422

Mycobacterium manipulate glutaminase 1 mediated glutaminolysis to regulate macrophage autophagy for bacteria intracellular survival.

Jialin Yu, Na Yan, Zhaoqian Gong, Qinmei Ma, Jing Liu, Xiaoling Wu, Guangcun Deng.

  Autophagy plays a vital role in eliminating intracellular mycobacterium. It is regulated by multiple metabolic processes including glutaminolysis. Glutaminase 1 (GLS1) is the rate-limiting enzyme of glutaminolysis and has been reported to control intracellular Gln content. However, its function on regulating autophagy in mycobacterium infected macrophage is still obscure. Hence, the current study hired mycobacterium virulent strain H37Rv or attenuated strain BCG to infect macrophage and detected the changes in cell glutaminolysis. The function of GLS1 on regulating autophagy in mycobacterium infected macrophages was further investigated. The results showed that BCG infection promoted macrophage autophagy, enhanced glutaminolysis, reduced intracellular Gln content, accompanied with the up-regulation of GLS1. Conversely, H37Rv infection resulted in completely opposite effects. Meanwhile, knockdown of GLS1 increased Gln content and attenuated autophagy in BCG infected macrophages. In addition, the deprivation of Gln not only promoted the autophagy of H37Rv infected macrophages, but also abolished the effect of knockdown GLS1 on regulating BCG infection-induced mTOR activation or autophagy. To sum up, our study suggested that different virulent strains of mycobacterium infection have totally opposite effects on glutaminolysis and the expression of GLS1. Specifically, mycobacterium virulent strain reduced GLS1 expression and decreased Gln content but mycobacterium attenuated strain promoted GLS1 expression and enhanced Gln content. Furthermore, GLS1 inhibits the activation of the mTOR signaling pathway and promotes autophagy by decreasing Gln content.

Keywords:  Autophagy; GLS1;; Glutaminolysis; Macrophage; mycobacterium

DOI:  https://doi.org/10.1016/j.cellsig.2024.111422
JCI Insight. 2024 Aug 13. pii: e178453. [Epub ahead of print]9(18):

Pyruvate metabolism dictates fibroblast sensitivity to GLS1 inhibition during fibrogenesis.

Greg Contento, Jo-Anne Am Wilson, Brintha Selvarajah, Manuela Platé, Delphine Guillotin, Valle Morales, Marcello Trevisani, Vanessa Pitozzi, Katiuscia Bianchi, Rachel C Chambers.

  Fibrosis is a chronic disease characterized by excessive extracellular matrix production, which leads to disruption of organ function. Fibroblasts are key effector cells of this process, responding chiefly to the pleiotropic cytokine transforming growth factor-β1 (TGF-β1), which promotes fibroblast to myofibroblast differentiation. We found that extracellular nutrient availability profoundly influenced the TGF-β1 transcriptome of primary human lung fibroblasts and that biosynthesis of amino acids emerged as a top enriched TGF-β1 transcriptional module. We subsequently uncovered a key role for pyruvate in influencing glutaminase (GLS1) inhibition during TGF-β1-induced fibrogenesis. In pyruvate-replete conditions, GLS1 inhibition was ineffective in blocking TGF-β1-induced fibrogenesis, as pyruvate can be used as the substrate for glutamate and alanine production via glutamate dehydrogenase (GDH) and glutamic-pyruvic transaminase 2 (GPT2), respectively. We further show that dual targeting of either GPT2 or GDH in combination with GLS1 inhibition was required to fully block TGF-β1-induced collagen synthesis. These findings embolden a therapeutic strategy aimed at additional targeting of mitochondrial pyruvate metabolism in the presence of a glutaminolysis inhibitor to interfere with the pathological deposition of collagen in the setting of pulmonary fibrosis and potentially other fibrotic conditions.

Keywords:  Cell biology; Collagens; Fibrosis; Glucose metabolism; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.178453
J Dermatol Sci. 2024 Aug 25. pii: S0923-1811(24)00174-9. [Epub ahead of print]

Staphylococcus epidermidis augments human β-defensin-3 synthesis through the transforming growth factor alpha-epidermal growth factor receptor cascade.

Rie Ommori, Satoru Shinkuma, Hideo Asada.

  BACKGROUND: Epidermal growth factor receptor inhibitors (EGFRIs) reduce β-defensin 3 (BD3) from keratinocytes stimulated by S. epidermidis, potentially leading to the development of acneiform rashes in patients undergoing EGFRIs treatment. However, the mechanism through which S. epidermidis induces BD3 via EGFR remains incompletely understood.OBJECTIVE: To elucidate the BD3 production pathway triggered by S. epidermidis.
METHODS: To assess the impact of S. epidermidis on EGFR ligand expression, the levels of released EGFR ligands in the keratinocyte culture medium following S. epidermidis stimulation were quantified using ELISA. Subsequently, to confirm the synergistic effect of TGF-α and S. epidermidis, we administered S. epidermidis and TGF-α to the keratinocyte culture medium and measured the expression levels of BD3. In addition, we stimulated Toll-like receptor 2 (TLR2)-knockdown keratinocytes with S. epidermidis and measured the expression levels of TGF-α.
RESULTS: While S. epidermidis did not induce EGF and HB-EGF, they increased TGF-α. The expression of BD3 was higher in keratinocytes stimulated by S. epidermidis in the presence of TGF-α, as compared to its absence. Moreover, both S. epidermidis- and TGF-α-induced BD3 were significantly suppressed by cetuximab. The expression levels of TGF-α induced by S. epidermidis were reduced in TLR2-knockdown keratinocytes CONCLUSION: Our findings suggest that S. epidermidis induces the expression of TGF-α in keratinocytes through TLR2, which, in cooperation with TGF-α, stimulates the production of BD3.

Keywords:  Acneiform rashes; Epidermal growth factor receptor inhibitor; Human β-defensin; S. epidermidis; TGF-α

DOI:  https://doi.org/10.1016/j.jdermsci.2024.08.003
J Biochem. 2024 Sep 24. pii: mvae064. [Epub ahead of print]

BACH to the ferroptosis.

Fuminori Tokunaga.

  Ferroptosis is regulated cell death characterized by iron-dependent phospholipid peroxidation, and is closely related to various diseases. System Xc -, a cystine/glutamate antiporter, and glutathione peroxidase 4 (GPX4) are the key molecules in ferroptosis. Erastin and RSL3, known as inhibitors of system Xc - and GPX4, respectively, are commonly used as ferroptosis inducers. BTB and CNC homology 1 (BACH1), a heme-binding transcription repressor, promotes pro-ferroptotic signaling, and therefore, Bach1-deficient cells are resistant to ferroptosis. Irikura et al. constructed Bach1-re-expressing immortalized mouse embryonic fibroblasts (iMEFs) from Bach1-/- mice, which induce ferroptosis simply by the depletion of 2-mercaptoethanol from the culture medium (J. Biochem. 2023; 174:239-252). Transcriptional repression by re-expressed BACH1 induces suppressed glutathione synthesis and increases labile iron. Furthermore, the ferroptosis initiated by BACH1-re-expressing iMEFs is propagated to surrounding cells. Thus, the BACH1-re-expression system is a novel and powerful tool to investigate the cellular basis of ferroptosis.

Keywords:  BACH1; ferroptosis; glutathione; system Xc−; transcriptional repression

DOI:  https://doi.org/10.1093/jb/mvae064
Cell Biochem Biophys. 2024 Sep 22.

Inhibition of FABP4 Ameliorates IL-13-Induced Inflammatory Response and Barrier Dysfunction in Nasal Mucosal Epithelial Cells through the Regulation of Ferroptosis.

Shanshan Qi.

  This study was conducted to investigate the role and the mechanism of fatty acid-binding protein 4 (FABP4) in allergic rhinitis (AR). To induce AR in vitro, human nasal epithelial cells (hNECs) were treated by interleukin (IL)-13. Real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blot were used to detect FABP4 expression. Enzyme-linked immunosorbent assay (ELISA) was used to detect the inflammatory level while inflammation-related proteins were detected by western blot. Immunofluorescence (IF) assay was used to detect mucin-5AC (MUC5AC) and zonula occludens-1 (ZO-1) level. The expressions of tight junction proteins were detected by western blot. Lipid reactive oxygen species (ROS) was detected using a BODIPY 581/591 C11 kit and iron level was detected by corresponding assay kits. Ferroptosis-related proteins were detected by western blot. With the goal of investigating the mechanism of FABP4 associated with ferroptosis, cells were pretreated by ferroptosis inducer erastin (30 mM) and rescue experiments were implemented. In this work, FABP4 expression was increased in hNECs treated by IL-13. After FABP4 was knocked down, the inflammation, mucus production, barrier dysfunction and ferroptosis induced by IL-13 in hNECs were all repressed. Nevertheless, erastin pre-treatment partially counteracted the protective role of FABP4 depletion against inflammation, mucus production and barrier dysfunction in IL-13-treated hNECs. In summary, FABP4 deficiency ameliorated IL-13-induced inflammatory response and barrier dysfunction in nasal mucosal epithelial cells through the regulation of ferroptosis.

Keywords:  Allergic rhinitis; Barrier dysfunction; FABP4; Ferroptosis; Inflammatory response

DOI:  https://doi.org/10.1007/s12013-024-01530-3
Science. 2024 Sep 27. 385(6716): 1428-1429

(Don't) take my breath away: Rare epithelial cells in our airways initiate reflexes to guard against harmful stimuli.

Laura Seeholzer.

Rare epithelial cells in our airways initiate reflexes to guard against harmful stimuli.

DOI: https://doi.org/10.1126/science.ads1317
Gels. 2024 Aug 23. pii: 545. [Epub ahead of print]10(9):

Topical Probiotic Hydrogels for Burn Wound Healing.

Tavinda Arshad, Varsha Mundrathi, Victoria E Perez, Jeilyn M Nunez, Hyunah Cho.

  Hydrogels have increasingly been used to enhance the effective healing of various wounds, including burn wounds. Similarly, the application of probiotics has recently been explored in wound healing and skin repairs. While probiotics have been consumed to provide therapeutic effects that aid with improving gut health, topical applications have been found to accelerate wound healing both in vitro and in vivo. For wounds that have complex healing mechanisms, such as burn wounds which depend on factors such as the depth of the burn, size of the afflicted area, and cause of the injury, probiotics with or without conventional therapeutic agents topically delivered via hydrogel technology are proven to be effective in the recovery of the damaged skin. This article aims to investigate the microorganisms present in the human skin microbiome and observe the effects of probiotics delivered by hydrogels on burn wound healing.

Keywords:  burn wound; hydrogels; probiotics; topical; wound healing

DOI:  https://doi.org/10.3390/gels10090545
Discov Med. 2024 Sep;36(188): 1911-1913

Antimicrobial Resistance: A Global Public Health Concern that Needs Perspective Combating Strategies and New Talented Antibiotics.

Abdelazeem Mohamed Algammal, Payam Behzadi.

No abstract present.

DOI: https://doi.org/10.24976/Discov.Med.202436188.177
J Allergy Clin Immunol. 2024 Sep 20. pii: S0091-6749(24)00985-0. [Epub ahead of print]

Mucosal Trained-Immunity Based Vaccines: Cutting Recurrent Infections in Autoimmune Patients on Immunosuppression.

Gloria Candelas, Ángela Villegas, Silvia Sánchez-Ramón.



Keywords:  Immunosuppressed Patients; Mucosal Vaccines; Recurrent Infections; Systemic Autoimmune Rheumatic Diseases; Trained Immunity

DOI:  https://doi.org/10.1016/j.jaci.2024.09.011
Curr Microbiol. 2024 Sep 23. 81(11): 372

Inflammatory Modulation Effects of Probiotics: A Safe and Promising Modulator for Cancer Prevention.

Mehran Mahooti, Elahe Abdolalipour, Samira Sanami, Davood Zare.

Chronic inflammation is the gate of many human illnesses and happens when the immune system is unable to suppress external attacks in the correct form. Nonetheless, the gut microbiome plays a pivotal role in keeping homeostasis in the human body and preventing inflammation. Imbalanced microbiota and many diseases can result in inflammation, which when not taken seriously, can be turned into chronic ones and ultimately lead to serious diseases such as cancer. One approach to maintaining hemostasis in the human body is consumption of probiotics as a supplement. Probiotics impact the immune functions of dendritic cells (DCs), T cells, and B cells in the gut-associated lymphoid tissue by inducing the secretion of an array of cytokines. They activate the innate immune response through their microbial-associated molecular pattern, and this activation is followed by multiple cytokine secretion and adaptive elicitation that mitigates pro-inflammatory expression levels and tumor incidence. Thus, according to several studies showing the benefit of probiotics application, alone or in combination with other agents, to induce potent immune responses in individuals against some inflammatory disorders and distinct types of cancers, this review is devoted to surveying the role of probiotics and the modulation of inflammation in some cancer models.

DOI: https://doi.org/10.1007/s00284-024-03901-8
Science. 2024 Sep 27. 385(6716): 1418-1420

Microbial hoolIgAn dismantles gut defenses.

Emma Slack.

Immunoglobulin degradation by a gut bacterium causes immunodeficiency in mice.

DOI: https://doi.org/10.1126/science.ads2152
J Neuroinflammation. 2024 Sep 20. 21(1): 233

Repeated LPS induces training and tolerance of microglial responses across brain regions.

Jennifer Kim, Olivia Sullivan, Kristen Lee, Justin Jao, Juan Tamayo, Abdullah Muhammad Madany, Brandon Wong, Paul Ashwood, Annie Vogel Ciernia.

  BACKGROUND: Neuroinflammation is involved in the pathogenesis of almost every central nervous system disorder. As the brain's innate immune cells, microglia fine tune their activity to a dynamic brain environment. Previous studies have shown that repeated bouts of peripheral inflammation can trigger long-term changes in microglial gene expression and function, a form of innate immune memory.METHODS AND RESULTS: In this study, we used multiple low-dose lipopolysaccharide (LPS) injections in adult mice to study the acute cytokine, transcriptomic, and microglia morphological changes that contribute to the formation of immune memory in the frontal cortex, hippocampus, and striatum, as well as the long-term effects of these changes on behavior. Training and tolerance of gene expression was shared across regions, and we identified 3 unique clusters of DEGs (2xLPS-sensitive, 4xLPS-sensitive, LPS-decreased) enriched for different biological functions. 2xLPS-sensitive DEG promoters were enriched for binding sites for IRF and NFkB family transcription factors, two key regulators of innate immune memory. We quantified shifts in microglia morphological populations and found that while the proportion of ramified and rod-like microglia mostly remained consistent within brain regions and sexes with LPS treatment, there was a shift from ameboid towards hypertrophic morphological states across immune memory states and a dynamic emergence and resolution of events of microglia aligning end-to-end with repeated LPS.
CONCLUSIONS: Together, findings support the dynamic regulation of microglia during the formation of immune memories in the brain and support future work to exploit this model in brain disease contexts.

Keywords:  Gene expression; Gene regulation; Innate immune memory; Microglia; Microglia morphology

DOI:  https://doi.org/10.1186/s12974-024-03198-1