bims-bac4me 2025-04-27 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–04–27
29 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Factor XII-driven coagulation traps bacterial infections.
Exploring CD169+ Macrophages as Key Targets for Vaccination and Therapeutic Interventions.
Cellular and Molecular Mechanisms of Innate Memory Responses.
Bidirectional Communication Between the Innate and Adaptive Immune Systems.
Butyrate-Producing Mixed Probiotics Alleviate MRSA-Induced Acute Lung Injury in Mice by Promoting M2 Macrophage Polarization.
Shigella-trained pro-inflammatory macrophages protect zebrafish from secondary infection.
A SpA+LukAB vaccine targeting Staphylococcus aureus evasion factors restricts infection in two minipig infection models.
Neonatal antibiotics impair infant vaccine responses.
Microglia endotoxin tolerance is retained after enforced repopulation.
The extracellular matrix protein periostin is required for wound repair in primary human airway epithelia.
Comprehensive single-cell RNA-sequencing study of Tollip deficiency effect in IL-13-stimulated human airway epithelial cells.
Barrier Integrity and Immunity: Exploring the Cutaneous Front Line in Health and Disease.
Maternal Administration of Probiotics Augments IL17-Committed γδ T Cells in the Newborn Lung.
MyD88-mediated signaling in intestinal fibroblasts regulates macrophage antimicrobial defense and prevents dysbiosis in the gut.
Antigen Uptake in the Gut: An Underappreciated Piece to the Puzzle?
Exogenous L-Serine Alleviates Pasteurella multocida-Induced Inflammation by Reprogramming the Transcription and Metabolism of Macrophages.
Thrombospondin-1 modulation by Bifidobacterium spp. mitigates lung damage in an acute lung injury mouse model.
The lung microbiome in interstitial lung disease.
Epitope-Based Vaccines: The Next Generation of Promising Vaccines Against Bacterial Infection.
Targeting epigenetic and post-translational modifications of NRF2: key regulatory factors in disease treatment.
IL-10 targets IRF transcription factors to suppress IFN and inflammatory response genes by epigenetic mechanisms.
Immunomodulating Effects of Heat-Killed Lactobacillus rhamnosus and Lactobacillus reuteri on Peripheral Blood Mononuclear Cells from Healthy Dogs.
Kinsenoside-Loaded Microneedle Accelerates Diabetic Wound Healing by Reprogramming Macrophage Metabolism via Inhibiting IRE1α/XBP1 Signaling Axis.
MAVS is a sensor of fumarate during antiviral immunity.
Therapeutic potential of ADSC-derived exosomes in acute lung injury by regulating macrophage polarization through IRF7/NLRP3 signaling.
Understanding chronic inflammation: couplings between cytokines, ROS, NO, Cai 2+, HIF-1α, Nrf2 and autophagy.
A type 1 immune-stromal cell network mediates disease tolerance against intestinal infection.
Lactiplantibacillus plantarum -derived extracellular vesicles alleviate acute lung injury by inhibiting ferroptosis of macrophages.
Amyloid precursor-like protein 2 expression in macrophages: differentiation and M1/M2 macrophage dynamics.

J Exp Med. 2025 Jul 07. pii: e20250049. [Epub ahead of print]222(7):

Factor XII-driven coagulation traps bacterial infections.

Katrin F Nickel, Anne Jämsä, Sandra Konrath, Praveen Papareddy, Lynn M Butler, Evi X Stavrou, Maike Frye, Mathias Gelderblom, Bernhard Nieswandt, Sven Hammerschmidt, Heiko Herwald, Thomas Renné.

Blood coagulation is essential for stopping bleeding but also drives thromboembolic disorders. Factor XII (FXII)-triggered coagulation promotes thrombosis while being dispensable for hemostasis, making it a potential anticoagulant target. However, its physiological role remains unclear. Here, we demonstrate that FXII-driven coagulation enhances innate immunity by trapping pathogens and restricting bacterial infection in mice. Streptococcus pneumoniae infection was more severe in FXII-deficient (F12-/-) mice, with increased pulmonary bacterial burden, systemic spread, and mortality. Similarly, Staphylococcus aureus skin infections and systemic dissemination were exacerbated in F12-/- mice. Reconstitution with human FXII restored bacterial containment. Plasma kallikrein amplifies FXII activation, and its deficiency aggravated S. aureus skin infections, similarly to F12-/- mice. FXII deficiency impaired fibrin deposition in abscess walls, leading to leaky capsules and bacterial escape. Bacterial long-chain polyphosphate activated FXII, triggering fibrin formation. Deficiency in FXII substrate factor XI or FXII/factor XI co-deficiency similarly exacerbated S. aureus infection. The data reveal a protective role for FXII-driven coagulation in host defense, urging caution in developing therapeutic strategies targeting this pathway.

DOI: https://doi.org/10.1084/jem.20250049
Vaccines (Basel). 2025 Mar 20. pii: 330. [Epub ahead of print]13(3):

Exploring CD169+ Macrophages as Key Targets for Vaccination and Therapeutic Interventions.

Rianne G Bouma, Aru Z Wang, Joke M M den Haan.

  CD169 is a sialic acid-binding immunoglobulin-like lectin (Siglec-1, sialoadhesin) that is expressed by subsets of tissue-resident macrophages and circulating monocytes. This receptor interacts with α2,3-linked Neu5Ac on glycoproteins as well as glycolipids present on the surface of immune cells and pathogens. CD169-expressing macrophages exert tissue-specific homeostatic functions, but they also have opposing effects on the immune response. CD169+ macrophages act as a pathogen filter, protect against infectious diseases, and enhance adaptive immunity, but at the same time pathogens also exploit them to enable further dissemination. In cancer, CD169+ macrophages in tumor-draining lymph nodes are correlated with better clinical outcomes. In inflammatory diseases, CD169 expression is upregulated on monocytes and on monocyte-derived macrophages and this correlates with the disease state. Given their role in promoting adaptive immunity, CD169+ macrophages are currently investigated as targets for vaccination strategies against cancer. In this review, we describe the studies investigating the importance of CD169 and CD169+ macrophages in several disease settings and the vaccination strategies currently under investigation.

Keywords:  CD169; Siglec-1; adaptive immunity; antigen-presenting cells; dendritic cells; macrophages; sialoadhesin; therapeutic interventions; vaccines

DOI:  https://doi.org/10.3390/vaccines13030330
Annu Rev Immunol. 2025 Apr;43(1): 615-640

Cellular and Molecular Mechanisms of Innate Memory Responses.

Musa M Mhlanga, Stephanie Fanucchi, Mumin Ozturk, Maziar Divangahi.

  There has been an increasing effort to understand the memory responses of a complex interplay among innate, adaptive, and structural cells in peripheral organs and bone marrow. Trained immunity is coined as the de facto memory of innate immune cells and their progenitors. These cells acquire epigenetic modifications and shift their metabolism to equip an imprinted signature to a persistent fast-responsive functional state. Recent studies highlight the contribution of noncoding RNAs and modulation of chromatin structures in establishing this epigenetic readiness for potential immune perturbations. In this review, we discuss recent studies that highlight trained immunity-mediated memory responses emerging intrinsically in innate immune cells and as a complex interplay with other cells at the organ level. Lastly, we survey epigenetic contributors to trained immunity phenotypes-specifically, a recently discovered regulatory circuit coordinating the regulation of a key driver of trained immunity.

Keywords:  epigenetics; immunometabolism; innate immunity; noncoding RNA; organ-trained immunity; vaccine immunology

DOI:  https://doi.org/10.1146/annurev-immunol-101721-035114
Annu Rev Immunol. 2025 Apr;43(1): 489-514

Bidirectional Communication Between the Innate and Adaptive Immune Systems.

Kathrynne A Warrick, Charles N Vallez, Hannah E Meibers, Chandrashekhar Pasare.

  Effective bidirectional communication between the innate and adaptive immune systems is crucial for tissue homeostasis and protective immunity against infections. The innate immune system is responsible for the early sensing of and initial response to threats, including microbial ligands, toxins, and tissue damage. Pathogen-related information, detected primarily by the innate immune system via dendritic cells, is relayed to adaptive immune cells, leading to the priming and differentiation of naive T cells into effector and memory lineages. Memory T cells that persist long after pathogen clearance are integral for durable protective immunity. In addition to rapidly responding to reinfections, memory T cells also directly instruct the interacting myeloid cells to induce innate inflammation, which resembles microbial inflammation. As such, memory T cells act as newly emerging activators of the innate immune system and function independently of direct microbial recognition. While T cell-mediated activation of the innate immune system likely evolved as a protective mechanism to combat reinfections by virulent pathogens, the detrimental outcomes of this mechanism manifest in the forms of autoimmunity and other T cell-driven pathologies. Here, we review the complexities and layers of regulation at the interface between the innate and adaptive immune systems to highlight the implications of adaptive instruction of innate immunity in health and disease.

Keywords:  CAR-T cells; T cell memory; TNF superfamily; autoimmunity; cytokine storms; microbial defense; sterile inflammation

DOI:  https://doi.org/10.1146/annurev-immunol-083122-040624
Probiotics Antimicrob Proteins. 2025 Apr 24.

Butyrate-Producing Mixed Probiotics Alleviate MRSA-Induced Acute Lung Injury in Mice by Promoting M2 Macrophage Polarization.

Minghan Li, Tianxu Pan, Juntong Yu, Xueting Wang, Ruyi Gao, Ya Wang, Dongyu Zhao, Xinyi Zhou, Hongye Li, Jialin Guo, Nan Wang, Haibin Huang, Chunfeng Wang, Guilian Yang.

  Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen responsible for acute lung injury (ALI) and other respiratory diseases. Probiotics and their metabolic byproducts are essential regulators of the gut-lung axis. This study investigated the protective effects of a mixed probiotics combination (Ligilactobacillus salivarius H3, Bacillus stratosphericus J1366, and Priestia megaterium J1037), which demonstrated inhibitory activity against MRSA growth and biofilm formation in vitro, on MRSA-induced ALI in mice. Results indicated that MRSA infection exacerbated lung pathological damage (P < 0.001), oxidative stress, and inflammation, while also disrupting gut microbiota balance and impairing intestinal barrier integrity. In contrast, the mixed probiotics restored gut microbiota homeostasis, enhanced barrier function, and increased short-chain fatty acid (SCFA) levels in the gut and circulatory system, particularly butyrate (P < 0.05). These changes promoted the polarization of macrophages towards the anti-inflammatory M2 phenotype (P < 0.05), thereby reducing pulmonary bacterial load (P < 0.05) and alleviating inflammation. 16S rDNA sequencing revealed that mixed probiotics diminished the prevalence of Staphylococcus (P < 0.001) in the gut, while fostering the proliferation of beneficial genera such as Lactobacillus (P < 0.001) and Bifidobacterium (P < 0.05). Notably, while vancomycin treatment reduced lung bacterial load (P < 0.05) and inflammation, it aggravated gut microbiota imbalance and barrier damage. These findings indicate that administering mixed probiotics prevents MRSA-induced ALI by regulating the gut-lung axis, providing a potential alternative to antibiotics in managing bacterial pneumonia.

Keywords:  Acute lung injury; Butyrate; Gut-lung axis; MRSA; Mixed probiotics

DOI:  https://doi.org/10.1007/s12602-025-10520-7
Cell Rep. 2025 Apr 22. pii: S2211-1247(25)00372-9. [Epub ahead of print]44(5): 115601

Shigella-trained pro-inflammatory macrophages protect zebrafish from secondary infection.

Margarida C Gomes, Dominik Brokatzky, Serge Mostowy.

  Shigella is an important human pathogen that has no licensed vaccine. Despite decades of seminal work suggesting that its pathogenicity relies on inflammatory cell death of macrophages, the in vivo role of macrophages in controlling Shigella infection remains poorly understood. Here, we use a zebrafish model of innate immune training to investigate the antibacterial role of macrophages following a non-lethal Shigella infection. We found that macrophages are crucial for zebrafish larvae survival during secondary Shigella infection. Consistent with signatures of trained immunity, we demonstrate that bacteria are cleared during training and that protection is independent of the secondary infection site. We show that following Shigella training, macrophages have altered mono- and tri-methylation on lysine 4 in histone 3 (H3K4me1/me3) deposition and shift toward a pro-inflammatory state, characterized by increased tumor necrosis factor alpha (TNF-α) expression and antibacterial reactive oxygen species (ROS) production. We conclude that macrophages are epigenetically reprogrammed by Shigella infection to enhance pro-inflammatory and protective responses.

Keywords:  CP: Immunology; CP: Microbiology; Shigella; infection biology; macrophages; trained immunity; zebrafish

DOI:  https://doi.org/10.1016/j.celrep.2025.115601
NPJ Vaccines. 2025 Apr 20. 10(1): 78

A SpA+LukAB vaccine targeting Staphylococcus aureus evasion factors restricts infection in two minipig infection models.

Jan T Poolman, Victor J Torres, Dominique Missiakas, Suzanne P M Welten, Jeffrey Fernandez, Ashley L DuMont, Anna O'Keeffe, Sergey R Konstantinov, Brian Morrow, Peter Burghout, Jan Grijpstra, Miranda M C van Beers, Chakkumkal Anish, Michel Beurret, Jeroen Geurtsen, Pauline M L Rood, Oliver Koeberling, Miaomiao Shi, Germie P J M van den Dobbelsteen.

Staphylococcus aureus is a major cause of bacterial infection-related deaths. Increasing antimicrobial resistance highlights the urgent need for effective preventative strategies. Antibody-mediated opsonophagocytosis, the key mechanism for protection against S. aureus, is disabled by critical virulence factors such as Staphylococcal protein A (SpA) and leukocidin AB (LukAB). In our study, we combined genetically detoxified vaccine candidates SpA* and LukAB RARPR-33 with a TH1 adjuvant aiming to restore host antibody functionality. To evaluate these vaccine candidates, we developed both surgical site infection (SSI) and superficial wound infection (SWI) models in minipigs. Our results showed a significant reduction in bacterial load and systemic dissemination in the SSI model, while skin infection severity was markedly decreased after intradermal immunization in the SWI model. This study introduces a novel S. aureus vaccine strategy by targeting immune evasion factors SpA and LukAB, utilizing potent TH1 adjuvants, and employing minipig challenge models.

DOI: https://doi.org/10.1038/s41541-025-01119-8
Nat Rev Immunol. 2025 Apr 23.

Neonatal antibiotics impair infant vaccine responses.

Kirsty Minton.

DOI: https://doi.org/10.1038/s41577-025-01176-z
Brain Behav Immun. 2025 Apr 22. pii: S0889-1591(25)00144-8. [Epub ahead of print]

Microglia endotoxin tolerance is retained after enforced repopulation.

Tiago Medeiros-Furquim, Anneke Miedema, Edwin Schilder, Nieske Brouwer, Inge R Holtman, Susanne M Kooistra, Bart J L Eggen.

  Microglia are crucial for CNS homeostasis and are involved in a wide range of neurodegenerative and neuroinflammatory diseases. Systemic inflammation and infections can contribute to neurodegeneration later in life by affecting microglia. Like other innate immune cells, microglia can develop innate immune memory (IMM) in response to an inflammatory challenge, altering their response to subsequent stimuli. IMM can ameliorate or worsen CNS pathology, but it is unclear if IMM can be reversed to restore microglia functions. Here, we investigated whether microglia depletion-repopulation by inhibition of the colony-stimulating factor 1 receptor with BLZ945 reversed LPS-induced endotoxin tolerance in mice. Repopulated microglia displayed a reduced expression of homeostatic genes and genes related to mitochondrial respiration and TCA cycle metabolism and an increased expression of immune effector and activation genes. Nonetheless the blunted inflammatory gene response after LPS-preconditioning was retained after a depletion-repopulation cycle. Our study highlights the persistence of endotoxin tolerance in microglia after a depletion-repopulation cycle which might impact the potential effectiveness of strategies targeted at microglia depletion for clinical applications.

Keywords:  BLZ945; CSF1R; CSF1R-inhibitor; Depletion; Endotoxin tolerance; Innate immune memory; Microglia; Neuroinflammation; Repopulation; Sotuletinib

DOI:  https://doi.org/10.1016/j.bbi.2025.04.014
Am J Physiol Lung Cell Mol Physiol. 2025 Apr 21.

The extracellular matrix protein periostin is required for wound repair in primary human airway epithelia.

Lorena A Tran, Michael Catlin, Scott Schecter, Andrew L Thurman, Shreya Ghimire, Rosarie Tudas, Brandon Bettis, Ryan Gannon, Joseph Zabner, Alejandro A Pezzulo.

  Type 2 inflammation and epithelial-to-mesenchymal transitions (EMTs) play critical roles in airway repair after damage from allergens or parasites. The matricellular protein periostin (POSTN) has increased expression in inflammatory conditions and has been implicated in fibrosis and EMT, suggesting a role in airway repair. This study investigates the role of periostin in airway epithelial and lung fibroblast wound repair using an in vitro wound model. Our results demonstrate that the type 2 cytokine IL-13 induces periostin secretion from primary human airway epithelial basal cells. Periostin knockdown in human airway epithelial cells (HAEs) and human lung fibroblasts (HLFs) impairs wound closure, indicating that periostin is required for airway repair. In a coculture model of HAE and HLFs, fibroblast-secreted POSTN is required for airway epithelial wound repair, suggesting that periostin is involved in paracrine signaling between the two cell types. These findings highlight periostin's critical function in epithelial and fibroblast-mediated wound repair, suggesting its potential as a therapeutic target for diseases characterized by aberrant wound healing and fibrosis, such as asthma and idiopathic pulmonary fibrosis.

Keywords:  fibrosis; human airway epithelia; inflammation; periostin; wound repair

DOI:  https://doi.org/10.1152/ajplung.00039.2025
BMC Res Notes. 2025 Apr 23. 18(1): 194

Comprehensive single-cell RNA-sequencing study of Tollip deficiency effect in IL-13-stimulated human airway epithelial cells.

Grace Yihua Lee, Niccolette Schaunaman, Hamid Reza Nouri, Monica Kraft, Hong Wei Chu.

   OBJECTIVE: Toll-interacting protein (Tollip) suppresses excessive pro-inflammatory signaling, but its function in airway epithelial responses to IL-13, a key mediator in allergic diseases, remains unclear. This study investigates Tollip knockdown (TKD) effects in primary human airway epithelial cells using single-cell RNA sequencing, providing the first single-cell analysis of TKD and the first exploring its interaction with IL-13.
RESULTS: IL-13 treatment upregulated key genes, including SPDEF, MUC5AC, POSTN, ALOX15, and CCL26, confirming IL-13's effects and validating our methods. IL-13 reduced TNF-α signaling and epithelial-mesenchymal transition in certain cell types, suggesting a dual role in promoting type 2 inflammation while suppressing Th1-driven inflammation. Tollip deficiency alone significantly amplified TNF-α signaling and inflammatory pathways in goblet, club, and suprabasal cells. Comparisons between TKDIL13 vs IL13 and TKD vs CTR revealed that IL-13 does not substantially alter Tollip deficiency response in most cell types, reinforcing findings in TKD vs CTR. Tollip deficiency alters the response to IL-13 in a cell-type-specific manner, strongly downregulating TNF-α signaling in goblet cells but only weakly in basal and club cells. Tollip deficiency enhances IL-13's suppression of Th1 inflammatory responses in goblet cells. These novel insights in Tollip-IL-13 interactions offer potential therapeutic targets for asthma and related diseases.

Keywords:  Basal cells; Epithelial–mesenchymal transition; IL13 or IL-13; Inflammatory response; TNF-α signaling; Tollip; scRNA-seq

DOI:  https://doi.org/10.1186/s13104-025-07255-7
Annu Rev Immunol. 2025 Apr;43(1): 219-252

Barrier Integrity and Immunity: Exploring the Cutaneous Front Line in Health and Disease.

Keitaro Fukuda, Yoshihiro Ito, Masayuki Amagai.

  Immune responses are influenced by not only immune cells but also the tissue microenvironment where these cells reside. Recent advancements in understanding the underlying molecular mechanisms and structures of the epidermal tight junctions (TJs) and stratum corneum (SC) have significantly enhanced our knowledge of skin barrier functions. TJs, located in the granular layer of the epidermis, are crucial boundary elements in the differentiation process, particularly in the transition from living cells to dead cells. The SC forms from dead keratinocytes via corneoptosis and features three distinct pH zones critical for barrier function and homeostasis. Additionally, the SC-skin microbiota interactions are crucial for modulating immune responses and protecting against pathogens. In this review, we explore how these components contribute both to healthy and disease states. By targeting the skin barrier in therapeutic strategies, we can enhance its integrity, modulate immune responses, and ultimately improve outcomes for patients with inflammatory skin conditions.

Keywords:  corneoptosis; hair follicle; pH; skin microbiota; stratum corneum; tight junction

DOI:  https://doi.org/10.1146/annurev-immunol-082323-030832
Eur J Immunol. 2025 Apr;55(4): e202451051

Maternal Administration of Probiotics Augments IL17-Committed γδ T Cells in the Newborn Lung.

Yohannes Tafesse, Arnaud Köhler, Guillem Sanchez Sanchez, Patricia Brito Rodrigues, Marko Verce, Panagiotis Vitsos, Isoline Verdebout, Moosa Rezwani, Maria Papadopoulou, Amandine Everard, Véronique Flamand, David Vermijlen.

  The early life period is increasingly being recognized as a window of opportunity to shape immunity, where microbiota and related probiotics have an important impact. Innate γδ T cells are the first T cells generated in utero, populating epithelial tissues such as the lung and contributing to tissue protection through, for example, IL17 production. Here, we studied the influence of maternal microbiota and probiotic supplementation during pregnancy on innate γδ T cells in the lung and thymus of newborn mice. Detailed time-kinetic experiments showed that at birth, the murine lung T cell population was specifically dominated by IL17-committed γδ T cells expressing an invariant Vγ6Vδ1 TCR. Single-cell RNA-sequencing showed that the biased IL17-commitment of perinatal lung γδT cells is highly conserved between mice and humans. While maternal microbiota depletion with antibiotics tended to decrease the frequency of the lung Vγ6 T cells of the offspring at birth, the maternal administration of Lacticaseibacillus rhamnosus (L.rhm.), but not of Bifidobacterium animalis subsp. lactis (B.lac.), increased significantly their frequency, resulting in the augmentation of the IL17-commitment of the mouse lung T cell compartment. Altogether, our data indicate that the maternal microbiota contributes to the shaping of IL17-committed γδT cells in the lungs of newborns and that maternal administration of specific probiotic strains can enhance this process.

Keywords:  early life; fetal; gammadelta; microbiota; probiotics

DOI:  https://doi.org/10.1002/eji.202451051
Cell Rep. 2025 Apr 20. pii: S2211-1247(25)00324-9. [Epub ahead of print]44(5): 115553

MyD88-mediated signaling in intestinal fibroblasts regulates macrophage antimicrobial defense and prevents dysbiosis in the gut.

Marina Chulkina, Hanh Tran, Gabriela Uribe, Steven Bruce McAninch, Christina McAninch, Ashley Seideneck, Bing He, Matthew Lanza, Kamil Khanipov, Georgiy Golovko, Don W Powell, Emily R Davenport, Irina V Pinchuk.

  Fibroblasts that reside in the gut mucosa are among the key regulators of innate immune cells, but their role in the regulation of the defense functions of macrophages remains unknown. MyD88 is suggested to shape fibroblast responses in the intestinal microenvironment. We found that mice lacking MyD88 in fibroblasts showed a decrease in the colonic antimicrobial defense, developing dysbiosis and aggravated dextran sulfate sodium (DSS)-induced colitis. These pathological changes were associated with the accumulation of Arginase 1+ macrophages with low antimicrobial defense capability. Mechanistically, the production of interleukin (IL)-6 and CCL2 downstream of MyD88 was critically involved in fibroblast-mediated support of macrophage antimicrobial function, and IL-6/CCL2 neutralization resulted in the generation of macrophages with decreased production of the antimicrobial peptide cathelicidin and impaired bacterial clearance. Collectively, these findings revealed a critical role of fibroblast-intrinsic MyD88 signaling in regulating macrophage antimicrobial defense under colonic homeostasis, and its disruption results in dysbiosis, predisposing the host to the development of intestinal inflammation.

Keywords:  CP: Immunology; MyD88; antimicrobial defense; dysbiosis; fibroblasts; gut; macrophages

DOI:  https://doi.org/10.1016/j.celrep.2025.115553
Annu Rev Immunol. 2025 Apr;43(1): 571-588

Antigen Uptake in the Gut: An Underappreciated Piece to the Puzzle?

Devesha H Kulkarni, Rodney D Newberry.

  The mammalian gut is a vast, diverse, and dynamic single-layer epithelial surface exposed to trillions of microbes, microbial products, and the diet. Underlying this epithelium lies the largest collection of immune cells in the body; these cells encounter luminal substances to generate antigen-specific immune responses characterized by tolerance at homeostasis and inflammation during enteric infections. How the outcomes of antigen-specific tolerance and inflammation are appropriately balanced is a central question in mucosal immunology. Furthermore, how substances large enough to generate antigen-specific responses cross the epithelium and encounter the immune system in homeostasis and during inflammation remains largely unexplored. Here we discuss the challenges presented to the gut immune system, the identified pathways by which luminal substances cross the epithelium, and insights suggesting that the pathways used by substances to cross the epithelium affect the ensuing immune response.

Keywords:  antigen; goblet cell; intestine; microfold cell; paracellular transport; transepithelial dendrite

DOI:  https://doi.org/10.1146/annurev-immunol-082523-090154
Vet Sci. 2025 Mar 07. pii: 254. [Epub ahead of print]12(3):

Exogenous L-Serine Alleviates Pasteurella multocida-Induced Inflammation by Reprogramming the Transcription and Metabolism of Macrophages.

Fang He, Zhengchun Lang, Yanlan Huang, Yangyang Qiu, Pan Xiong, Nengzhang Li, Guangfu Zhao, Yuanyi Peng.

  P. multocida is notorious for inducing excessive inflammation with high lethality in multiple animals, such as cattle, pigs, and chickens. Our previous study revealed that L-serine was decreased in the lungs of mice infected with P. multocida capsular type A strain CQ2 (PmCQ2), and 2 mg/kg of L-serine could alleviate PmCQ2-induced lung inflammation in vivo, which may largely depend on macrophages. However, the underlying intrinsic alterations remain unknown. Here, we demonstrated that 10 mM of L-serine significantly inhibited the release of inflammatory cytokines (e.g., IL-1β and TNF-α) by blocking inflammasome activation (including NALP1, NLRP3, NLRC4, AIM2, and Caspase-1) in PmCQ2-infected macrophages. Furthermore, the results of RNA-seq and metabonomics revealed that exogenous L-serine supplementation substantially reprogrammed macrophage transcription and metabolism. Mechanically, L-serine reduced inflammatory responses via the inhibition of glycolysis in macrophages based on a seahorse assay. Together, these findings characterize the intrinsic molecular alterations in activated macrophages and provide new targets for modulating P. multocida infection-induced macrophage inflammation.

Keywords:  L-serine; Pasteurella multocida; inflammasome; macrophage; metabolic reprogramming

DOI:  https://doi.org/10.3390/vetsci12030254
Microbiol Res. 2025 Apr 15. pii: S0944-5013(25)00129-6. [Epub ahead of print]297 128173

Thrombospondin-1 modulation by Bifidobacterium spp. mitigates lung damage in an acute lung injury mouse model.

Yumin Kim, Min Seo Ki, Mi Hwa Shin, Ji Soo Choi, Moo Suk Park, Yeongmin Kim, Chang-Myung Oh, Sang Hoon Lee.

  Our study shows that Bifidobacterium spp. supplementation reduces lung damage in acute lung injury by enhancing immune cell activity and restoring thrombospondin-1 levels, offering a promising therapeutic approach for the treatment of ALI/ARDS.
BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are critical conditions characterized by severe lung inflammation and damage, often exacerbated by mechanical ventilation. Probiotics, particularly those containing Bifidobacterium spp. (Bifidus) have shown promise in modulating immune responses and reducing inflammation.
METHODS: In this study, we investigated the effects of Bifidus supplementation in a mouse model of lipopolysaccharide induced ALI and ventilator-induced lung injury.
RESULTS: Our results demonstrate that Bifidus significantly ameliorates lung injury by enhancing efferocytosis and reducing pro-inflammatory cytokine levels. Single-cell RNA sequencing revealed significant changes in lung immune cell populations, particularly macrophages and monocytes, which showed increased efferocytosis activity and modulation of key signaling pathways such as TNF, MAPK and TLR. Notably, Bifidus feeding restored thrombospondin-1 levels in lung tissue, facilitating clearance of apoptotic cells and promoting resolution of inflammation.
CONCLUSIONS: Overall, our study highlights the potential of Bifidus as a therapeutic strategy to mitigate lung injury in ALI/ARDS.

Keywords:  Acute lung injury; Bifidobacterium; Gut-Lung axis; Thrombospondin-1

DOI:  https://doi.org/10.1016/j.micres.2025.128173
Breathe (Sheff). 2025 Apr;21(2): 240167

The lung microbiome in interstitial lung disease.

Sheridan G Mikhail, David N O'Dwyer.

Interstitial lung disease (ILD) is a heterogeneous chronic form of lung disease. The pathogenesis of ILD is poorly understood and a common form of ILD, idiopathic pulmonary fibrosis (IPF) is associated with poor prognosis. There is evidence for substantial dysregulated immune responses in ILD. The microbiome is a key regulator of the immune response, and the lung microbiome correlates with alveolar immunity and clinical outcomes in ILD. Most observational lung microbiome studies have been conducted in patients with IPF. A consistent observation in these studies is that the bacterial burden of the lung is elevated in patients with IPF and predicts mortality. However, our understanding of the mechanism is incomplete and our understanding of the role of the lung microbiome in other forms of ILD is limited. The microbiomes of the oropharynx and gut may have implications for the lung microbiome and pulmonary immunity in ILD but require substantial further research. Here, we discuss the studies supporting a role for the lung microbiome in the pathogenesis of IPF, and briefly describe the putative role of the oral-lung axis and the gut-lung axis in ILD.

DOI: https://doi.org/10.1183/20734735.0167-2024
Vaccines (Basel). 2025 Feb 27. pii: 248. [Epub ahead of print]13(3):

Epitope-Based Vaccines: The Next Generation of Promising Vaccines Against Bacterial Infection.

Jing Li, Yan Ju, Min Jiang, Sha Li, Xiao-Yan Yang.

  The increasing resistance of bacteria to antibiotics has underscored the need for new drugs or vaccines to prevent bacterial infections. Reducing multidrug resistance is a key objective of the WHO's One Health initiative. Epitopes, the key parts of antigen molecules that determine their specificity, directly stimulate the body to produce specific humoral and/or cellular immune responses. Epitope-based vaccines, which combine dominant epitopes in a rational manner, induce a more efficient and specific immune response than the original antigen. While these vaccines face significant challenges, such as epitope escape or low immunogenicity, they offer advantages including minimal adverse reactions, improved efficacy, and optimized protection. As a result, epitope-based vaccines are considered a promising next-generation approach to combating bacterial infections. This review summarizes the latest advancements, challenges, and future prospects of epitope-based vaccines targeting bacteria, with a focus on their development workflow and application in antibiotic-resistant pathogens with high mortality rates, including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. The goal of this review is to provide insights into next-generation vaccination strategies to combat bacterial infections associated with antibiotic resistance and high mortality rates.

Keywords:  B-cell epitopes; Staphylococcus aureus; T-cell epitopes; bacterial vaccines; epitope-based vaccines

DOI:  https://doi.org/10.3390/vaccines13030248
Cell Death Discov. 2025 Apr 21. 11(1): 189

Targeting epigenetic and post-translational modifications of NRF2: key regulatory factors in disease treatment.

Xinyi Yang, Yingchao Liu, Jinghao Cao, Cuiyun Wu, Lusheng Tang, Wenxia Bian, Yuhan Chen, Lingyan Yu, Yunyi Wu, Sainan Li, Yuhuan Shen, Jun Xia, Jing Du.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor involved in regulating cellular antioxidant defense and detoxification mechanisms. It mitigates oxidative stress and xenobiotic-induced damage by inducing the expression of cytoprotective enzymes, including HO-1 and NQO1. NRF2 also modulates inflammatory responses by inhibiting pro-inflammatory genes and mediates cell death pathways, including apoptosis and ferroptosis. Targeting NRF2 offers potential therapeutic avenues for treating various diseases. NRF2 is regulated through two principal mechanisms: post-translational modifications (PTMs) and epigenetic alterations. PTMs, including phosphorylation, ubiquitination, and acetylation, play a pivotal role in modulating NRF2's stability, activity, and subcellular localization, thereby precisely controlling its function in the antioxidant response. For instance, ubiquitination can lead to NRF2 degradation and reduced antioxidant activity, while deubiquitination enhances its stability and function. Epigenetic modifications, such as DNA methylation, histone modifications, and interactions with non-coding RNAs (e.g., MALAT1, PVT1, MIR4435-2HG, and TUG1), are essential for regulating NRF2 expression by modulating chromatin architecture and gene accessibility. This paper systematically summarizes the molecular mechanisms by which PTMs and epigenetic alterations regulate NRF2, and elucidates its critical role in cellular defense and disease. By analyzing the impact of PTMs, such as phosphorylation, ubiquitination, and acetylation, as well as DNA methylation, histone modifications, and non-coding RNA interactions on NRF2 stability, activity, and expression, the study reveals the complex cellular protection network mediated by NRF2. Furthermore, the paper explores how these regulatory mechanisms affect NRF2's roles in oxidative stress, inflammation, and cell death, identifying novel therapeutic targets and strategies. This provides new insights into the treatment of NRF2-related diseases, such as cancer, neurodegenerative disorders, and metabolic syndrome. This research deepens our understanding of NRF2's role in cellular homeostasis and lays the foundation for the development of NRF2-targeted therapies.

DOI: https://doi.org/10.1038/s41420-025-02491-z
Nat Immunol. 2025 Apr 22.

IL-10 targets IRF transcription factors to suppress IFN and inflammatory response genes by epigenetic mechanisms.

Bikash Mishra, Mahesh Bachu, Ruoxi Yuan, Claire Wingert, Vidyanath Chaudhary, Caroline Brauner, Richard Bell, Lionel B Ivashkiv.

Interleukin-10 (IL-10) is pivotal in suppressing innate immune activation, in large part by suppressing induction of inflammatory genes. Despite decades of research, the molecular mechanisms underlying this inhibition have not been resolved. Here we utilized an integrated epigenomic analysis to investigate IL-10-mediated suppression of LPS and TNF responses in primary human monocytes. Instead of inhibiting core TLR4-activated pathways such as NF-κB, MAPK-AP-1 and TBK1-IRF3 signaling, IL-10 targeted IRF transcription factor activity and DNA binding, particularly IRF5 and an IRF1-mediated amplification loop. This resulted in suppression of inflammatory NF-κB target genes and near-complete suppression of interferon-stimulated genes. Mechanisms of gene inhibition included downregulation of chromatin accessibility, de novo enhancer formation and IRF1-associated H3K27ac activating histone marks. These results provide a mechanism by which IL-10 suppresses inflammatory NF-κB target genes, highlight the role of IRF1 in inflammatory gene expression and describe the suppression of IFN responses by epigenetic mechanisms.

DOI: https://doi.org/10.1038/s41590-025-02137-3
Vet Sci. 2025 Mar 02. pii: 226. [Epub ahead of print]12(3):

Immunomodulating Effects of Heat-Killed Lactobacillus rhamnosus and Lactobacillus reuteri on Peripheral Blood Mononuclear Cells from Healthy Dogs.

Marie Cauquil, Thierry Olivry.

  Canine atopic dermatitis (AD) is a T-cell-driven inflammatory skin disease, characterized by an imbalance between the Th1 and Th2 immune responses. Probiotics (live bacteria) and postbiotics (inactivated, killed bacteria) have garnered attention for the management of AD in humans and dogs. Both probiotics and postbiotics possess immunomodulating properties that could be beneficial for allergic patients. This study aims to evaluate the immunomodulating effects of Tyndallized (heat-killed) postbiotics of Lactobacillus rhamnosus and Lactobacillus reuteri, which are active components of the Linkskin products (Nextmune, Palazzo Pignano, Cremona, Italy). Peripheral blood mononuclear cells (PBMCs) were isolated from healthy dogs and incubated separately with each postbiotic. The cytokine levels in the supernatants were measured before and after 12, 24, 48, and 72 h of incubation. Both Tyndallized lactobacilli significantly increased the levels of IL-12 and IFN-γ (Th1 cytokines) and IL-10 (associated with T regulatory cells), while the levels of the Th2 cytokine IL-4 remained stable. Overall, these two Lactobacillus postbiotics stimulated canine PBMCs to produce a cytokine profile typically associated with an anti-allergic response. Further studies are needed to evaluate the benefit of these postbiotics as an adjuvant for the reactive treatment or for the prevention of relapses of allergic flares in atopic dogs.

Keywords:  Lactobacillus; Tyndallized; atopic dermatitis; cytokines; dog; heat-killed bacteria; immunomodulation; postbiotics

DOI:  https://doi.org/10.3390/vetsci12030226
Adv Sci (Weinh). 2025 Apr 25. e2502293

Kinsenoside-Loaded Microneedle Accelerates Diabetic Wound Healing by Reprogramming Macrophage Metabolism via Inhibiting IRE1α/XBP1 Signaling Axis.

Li Lu, Jiewen Liao, Chao Xu, Yuan Xiong, Juan Zhou, Guangji Wang, Ze Lin, Kangkang Zha, Chuanlu Lin, Ruiyin Zeng, Guandong Dai, Qian Feng, Bobin Mi, Guohui Liu.

  Continuously bacterial infection, undue oxidative stress, and inflammatory responses in the skin tissue microenvironment determine the delayed healing outcome of diabetic wounds, which remain a tough clinical challenge and need multifaceted therapeutic strategies. In this work, HA-ADH/HA-QA-ALD-based hydrogel microneedle (HAQA-MN) with antimicrobial and antioxidative activities incorporating kinsenoside (KD) coated with macrophage membrane (M-KD) targeting inflammation relief is developed to improve the cutaneous micro-niche. KD is observed to trigger trimethylamine N-oxide-irritated proinflammatory macrophages repolarization from M1 state to anti-inflammatory M2 phenotype, and the underlying mechanism is due to drug-induced IRE1α/XBP1/HIF-1α pathway suppression, accompanied by diminution of glycolysis and enhancement of oxidative phosphorylation, resulting in proinflammatory cascade inhibition and anti-inflammatory signaling enhancement. The hydrazone cross-linked HAQA-MN possesses favorable biocompatibility, self-healing, controlled release of M-KD and excellent mechanical properties. Moreover, the MN patch remarkedly restrains the survival of E. coli and S. aureus and eliminates hydrogen peroxide to preserve cellular viability. Notably, M-KD@HAQA-MN array effectively ameliorates cutaneous inflammation and oxidative stress and facilitate angiogenesis and collagen deposition, thereby accelerating tissue regeneration of diabetic mice with a full-thickness skin defect model. Collectively, this study highlights a multifunctional MN platform as a promising candidate in clinical application for the treatment of diabetic wounds.

Keywords:  diabetic wound; inflammation; kinsenoside; macrophage; metabolic reprogramming; microneedle

DOI:  https://doi.org/10.1002/advs.202502293
Nat Microbiol. 2025 Apr 23.

MAVS is a sensor of fumarate during antiviral immunity.

Yukun Min, Luke A J O'Neill.

DOI: https://doi.org/10.1038/s41564-025-01991-z
Int Immunopharmacol. 2025 Apr 18. pii: S1567-5769(25)00648-4. [Epub ahead of print]156 114658

Therapeutic potential of ADSC-derived exosomes in acute lung injury by regulating macrophage polarization through IRF7/NLRP3 signaling.

Jingyi Ren, Guanhong Lei, Ajing Dong, Shuyan Cao, Xiao Han, Haibo Li.

  Alveolar macrophages (AMs) play a critical role in regulating pulmonary immunity and inflammation. Acute lung injury (ALI), frequently initiated by sepsis-induced systemic inflammation and cytokine storms, leads to heightened lung permeability and respiratory failure. Adipose-derived stem cell exosomes (ADSC-Exos) have shown promise as therapeutic agents due to their immunomodulatory properties. This study assesses the effectiveness of ADSC-Exos in mitigating ALI by modulating macrophage (mø) polarization and suppressing pyroptosis. In vivo, an LPS-induced ALI mouse model demonstrated that ADSC-Exos attenuated lung tissue inflammation and damage, as verified by histological staining, ELISA, and immunofluorescence. In vitro, LPS-stimulated MH-S cells treated with ADSC-Exos showed a decrease in M1 (iNOS, CD86) and an increase in M2 (CD206, Arg-1) markers, as evidenced by Western blotting (WB) and flow cytometry. Mechanistically, RNA sequencing pinpointed IRF7 as a key upstream regulator of pyroptosis. ADSC-Exos inhibited the NLRP3 inflammasome and pyroptosis, fostering a shift from pro-inflammatory M1 to anti-inflammatory M2 mø phenotypes. Overexpression of IRF7 negated these effects, undermining the protective role of ADSC-Exos. Notably, inhibition of exosome secretion with GW4869 nullified these immunomodulatory effects, underscoring the vital role of ADSC-Exos. This study underscores the therapeutic potential of ADSC-Exos in restoring alveolar mø homeostasis, modulating immune responses, and alleviating lung inflammatory injury in ALI. These findings suggest ADSC-Exos as a feasible strategy for treating sepsis-induced pulmonary complications.

Keywords:  Acute Lung Injury; Adipose Derived Stem Cells; Exosomes; Pyroptosis, Macrophage

DOI:  https://doi.org/10.1016/j.intimp.2025.114658
Front Immunol. 2025 ;16 1558263

Understanding chronic inflammation: couplings between cytokines, ROS, NO, Cai 2+, HIF-1α, Nrf2 and autophagy.

Krzysztof Piotr Michalak, Amelia Zofia Michalak.

  Chronic inflammation is an important component of many diseases, including autoimmune diseases, intracellular infections, dysbiosis and degenerative diseases. An important element of this state is the mainly positive feedback between inflammatory cytokines, reactive oxygen species (ROS), nitric oxide (NO), increased intracellular calcium, hypoxia-inducible factor 1-alpha (HIF-1α) stabilisation and mitochondrial oxidative stress, which, under normal conditions, enhance the response against pathogens. Autophagy and the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant response are mainly negatively coupled with the above-mentioned elements to maintain the defence response at a level appropriate to the severity of the infection. The current review is the first attempt to build a multidimensional model of cellular self-regulation of chronic inflammation. It describes the feedbacks involved in the inflammatory response and explains the possible pathways by which inflammation becomes chronic. The multiplicity of positive feedbacks suggests that symptomatic treatment of chronic inflammation should focus on inhibiting multiple positive feedbacks to effectively suppress all dysregulated elements including inflammation, oxidative stress, calcium stress, mito-stress and other metabolic disturbances.

Keywords:  HIF-1α; NF-κB; autophagy; calcium flux; cytokines; iNOS; inflammation; nitric oxide

DOI:  https://doi.org/10.3389/fimmu.2025.1558263
Cell. 2025 Apr 19. pii: S0092-8674(25)00395-2. [Epub ahead of print]

A type 1 immune-stromal cell network mediates disease tolerance against intestinal infection.

Susan Westfall, Maria E Gentile, Tayla M Olsen, Danielle Karo-Atar, Andrei Bogza, Franziska Röstel, Ryan D Pardy, Giordano Mandato, Ghislaine Fontes, De'Broski Herbert, Heather J Melichar, Valerie Abadie, Martin J Richer, Donald C Vinh, Joshua F E Koenig, Oliver J Harrison, Maziar Divangahi, Sebastian Weis, Alex Gregorieff, Irah L King.

  Type 1 immunity mediates host defense through pathogen elimination, but whether this pathway also impacts tissue function is unknown. Here, we demonstrate that rapid induction of interferon γ (IFNγ) signaling coordinates a multicellular response that is critical to limit tissue damage and maintain gut motility following infection of mice with a tissue-invasive helminth. IFNγ production is initiated by antigen-independent activation of lamina propria CD8+ T cells following MyD88-dependent recognition of the microbiota during helminth-induced barrier invasion. IFNγ acted directly on intestinal stromal cells to recruit neutrophils that limited parasite-induced tissue injury. IFNγ sensing also limited the expansion of smooth muscle actin-expressing cells to prevent pathological gut dysmotility. Importantly, this tissue-protective response did not impact parasite burden, indicating that IFNγ supports a disease tolerance defense strategy. Our results have important implications for managing the pathophysiological sequelae of post-infectious gut dysfunction and chronic inflammatory diseases associated with stromal remodeling.

Keywords:  IFNg; disease tolerance; gut motility; helminth; microbiota; stroma; tissue-resident memory cells

DOI:  https://doi.org/10.1016/j.cell.2025.03.043
J Nanobiotechnology. 2025 Apr 23. 23(1): 307

Lactiplantibacillus plantarum -derived extracellular vesicles alleviate acute lung injury by inhibiting ferroptosis of macrophages.

Qiong Zhao, Jingbo Lai, Yang Jiang, Enhai Cui, Hui Chang, Ruolang Pan, Ping Li, Jian-Zhong Shao, Jing Zheng, Ye Chen.

  Despite considerable advancements in understanding the mechanisms of ALI, the therapeutic options available in clinical practice remain predominantly supportive, highlighting the urgent need for innovative treatments. In this study, we investigated the potential protective benefits of extracellular vehicles from the probiotic strain Lactiplantibacillus plantarum (LpEVs) in ALI mouse model. We revealed that LpEVs administration attenuated LPS-induced ALI, as evidenced by reduced lung pathology, decreased inflammatory markers, and mitigated ferroptosis. In vitro experiments demonstrated that LpEVs restrained ferroptosis and promoted a shift towards an anti-inflammatory macrophage phenotype. Moreover, LpEVs increased the expression of NRF2, resulting in the promotion of HO1 and strengthening anti-ferroptotic System Xc-/GPX4 axis. Our analysis revealed that LpEVs alleviated ALI through the suppression of macrophages ferroptosis by delivering cbn-let-7 targeting ferroptosis-related gene Acsl4. These findings propose LpEVs as a promising therapeutic approach for preventing and treating ALI, highlighting the potential of leveraging probiotic-derived biomolecules to develop novel therapeutic strategies.

Keywords:   Lactiplantibacillus plantarum ; Acute lung injury; Extracellular vesicles; Ferroptosis; Macrophages

DOI:  https://doi.org/10.1186/s12951-025-03405-y
Front Oncol. 2025 ;15 1570955

Amyloid precursor-like protein 2 expression in macrophages: differentiation and M1/M2 macrophage dynamics.

Gabrielle L Brumfield, Shelby M Knoche, Kenadie R Doty, Alaina C Larson, Brittany J Poelaert, Don W Coulter, Joyce C Solheim.

  Amyloid precursor-like protein 2 (APLP2) has been previously associated with pro-tumor phenotypes in cancer cells, and in this current study we investigated the expression and functions of this protein in macrophages. Our findings showed that APLP2 expression was increased in monocyte-like U937 cells after cytokine-induced differentiation to macrophage-like cells. Evaluation of human mRNA data revealed that APLP2 is more highly expressed in human M2/anti-inflammatory (pro-tumor) macrophages than in M1 macrophages (which have a pro-inflammatory, anti-tumor phenotype). Consistent with the mRNA data, by immunoblotting we identified increased APLP2 protein expression in mouse M2/anti-inflammatory macrophages. Intratumoral infiltration of M2/anti-inflammatory macrophages has been reported in several cancers, including neuroblastoma (NB). We observed that treatment of macrophages with NB-conditioned media induced M2/anti-inflammatory and mixed phenotypes. Through comparison of macrophages from wild-type and APLP2-knockout mice, we correlated alterations in inflammation-associated markers with the presence of APLP2. This suggests that APLP2 influences macrophage polarization dynamics between M0/unpolarized and pro- and anti-inflammatory states, and populations altered by APLP2 KO resemble the macrophage profiles altered with NB-conditioned media treatment. In total, our work implicates APLP2 as a mediator of macrophage status, namely in the M0/unpolarized macrophage and the M1/pro-inflammatory and M2/anti-inflammatory axis.

Keywords:  M1; M2; amyloid precursor-like protein 2; cancer; differentiate; inflammation; macrophage; neuroblastoma

DOI:  https://doi.org/10.3389/fonc.2025.1570955