bims-bac4me 2025-05-25 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–05–25
twenty-one papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Immunometabolism shapes chronic Staphylococcus aureus infection: insights from biofilm infection models.
A restarted life: Resetting microglia innate immune memory.
The nasal microbiome in early infancy is primarily shaped by the maternal nasal microbiome.
Trained immunity driven by Enterococcus faecalis ribosomal protein S11 enhances antigen presentation and boosts influenza vaccine efficacy via nanoparticle delivery.
β-glucan induced trained immunity enhances antibody levels in a vaccination model in mice.
Characterization of type 2 interleukin-1 receptor (IL-1R2) as an inhibitory regulator of trained immunity in teleost.
Macrophage immunometabolism dysregulation and inflammatory disorders.
BCG Vaccination Reprograms the Function of M-MDSCs and Aggravates Necrotizing Enterocolitis in Neonates.
Colonization dynamics of Streptococcus pneumoniae are determined by polymorphisms in the BlpAB transporter.
Porcine nasal organoids to model interactions between the swine nasal microbiota and the host.
Antibiotics, microbiota and the calibration of infant vaccine responses.
NLRP3 regulates macrophage function by M-CSF/M-CSFR signaling in acute radiation-induced lung injury.
Impact of the maternal microbiome on neonatal immune development.
Microenvironmental Conditions and Serum Availability Alter Primary Human Macrophage NF-κB Inflammatory Response and Function.
Iron at the crossroads of host-microbiome interactions in health and disease.
Hosts and Commensal Bacteria Synergistically Antagonize Opportunistic Pathogens at the Single-Cell Resolution.
The clockwork macrophage: timing in innate immunity.
The biological activity and potential of probiotics-derived extracellular vesicles as postbiotics in modulating microbiota-host communication.
Exosomes derived from M2 macrophages regulate airway inflammation by modulating epithelial cell proliferation and apoptosis.
Probiotic DNA epigenetically upregulates epithelial PD-L1 via KDM5A-mediated demethylation to suppress airway allergy by inducing activated Th2 cell apoptosis.
Integrated proteomics and phosphoproteomics profiling dynamic signaling networks underlying two distinct types of macrophage activation.

Curr Opin Microbiol. 2025 May 22. pii: S1369-5274(25)00034-7. [Epub ahead of print]86 102612

Immunometabolism shapes chronic Staphylococcus aureus infection: insights from biofilm infection models.

Adedayo E Ogunware, Tammy Kielian.

Staphylococcus aureus is both a commensal bacterium and versatile pathogen, capable of transitioning from a benign colonizer to cause invasive disease. Its ability to form biofilm - a resilient, highly structured bacterial community - plays a key role in chronic infections, including those associated with medical implants and native tissues. The unique microenvironments of these biofilm niches create challenges for the host immune system, complicating pathogen clearance. Immunometabolism, the interplay between immune function and metabolic programming, plays a crucial role in dictating how the host combats S. aureus biofilms. Leukocytes undergo profound metabolic changes in response to biofilm, which can lead to dysregulated immune responses and persistent infection. This review explores recent insights defining the metabolic landscape of immune responses to S. aureus biofilm with a focus on two clinically relevant models, namely, craniotomy and prosthetic joint infection.

DOI: https://doi.org/10.1016/j.mib.2025.102612
Neurosci Biobehav Rev. 2025 May 14. pii: S0149-7634(25)00206-4. [Epub ahead of print]174 106206

A restarted life: Resetting microglia innate immune memory.

Fangyuan Cheng, Bo Yan, Fanglian Chen, Ping Lei.

  Microglia can achieve depletion and repopulation through various mechanisms, improving outcomes in multiple CNS diseases. Innate immune memory in microglia can undergo continuous reprogramming through epigenetics, facilitating iterative memory upgrades. Here, through a comprehensive literature review, we propose the concepts of the microglial innate immune memory prototype (MIIMP) and microglial temporally phased innate immune memory reset (MTPIIMR). The temporally phased innate immune memory are reflected not only in the formation of immune response prototypes in microglia but also in the partial reset of innate immune memory during the depletion and repopulation process. In the duel against time, single cycles of depletion and repopulation can yield benefits through partial innate immune memory reset, while multiple cycles accelerate microglial aging. Identifying the optimal solution to replace microglia for filling ecological niches and executing their functions perfectly is a formidable yet profoundly significant challenge.

Keywords:  CSF1R inhibitor; Innate immune memory; Microgia; Repopulation

DOI:  https://doi.org/10.1016/j.neubiorev.2025.106206
J Allergy Clin Immunol. 2025 May 16. pii: S0091-6749(25)00553-6. [Epub ahead of print]

The nasal microbiome in early infancy is primarily shaped by the maternal nasal microbiome.

Bailey E Quinn, José Alejandro Reyes Rodríguez, Emmanuel Kweku Sam, Jasmina Duliman, Elizabeth Denn, Sandra Lee, Liang Shan, Christiana Kuti, Beatrice Irene Nyann, Nicolas Rosario-Matos, Leyao Wang.

   BACKGROUND: The infant nasal microbiota closely mediates the risks of developing childhood respiratory diseases. However, the primary sources of these early residing bacteria remain largely unknown, preventing the development of microbiome strategies for disease prevention.
OBJECTIVE: Identify the primary maternal source of bacteria found in the early infant nasal microbiome.
METHODS: We conducted a birth cohort study, named Mother Infant Microbiome International Cohort (MIMIC). We recruited 95 mother-newborn dyads from three sites (St. Louis, Missouri, United States; San Juan, Puerto Rico; and Accra, Ghana) and collected samples at two time points (at birth and around two months of age). We performed analyses on 16S ribosomal RNA gene sequencing data to evaluate the maternal microbiomes (nasal, saliva, breast milk, and areola skin) as sources seeding the infant nasal microbiome.
RESULTS: The infant nasal microbiome underwent a major compositional change during the first two months of life. The maternal nasal microbiome was identified as the primary source of bacteria in the early nasal microbiome across the three regions. Corynebacterium was predominantly transferred from the maternal nasal microbiome. Infants were more likely to harbor a Corynebacterium-dominant nasal microbiome if their mother's nasal microbiome was Corynebacterium-dominant.
CONCLUSIONS: The maternal nasal microbiome is an important source of bacteria in the early nasal microbiome. A large portion of transmitted bacteria from the maternal nasal microbiome was a generally beneficial bacterial genus, Corynebacterium. Results from this study will aid the development of early life intervention strategies that aim to reduce the incidence of childhood respiratory diseases and asthma.

Keywords:  Africa; Corynebacterium; Ghana; MIMIC; Puerto Rico; childhood asthma; infant nasal microbiome; maternal sources; microbial transmission; respiratory viral infections

DOI:  https://doi.org/10.1016/j.jaci.2025.05.004
Int J Biol Macromol. 2025 May 15. pii: S0141-8130(25)04731-2. [Epub ahead of print] 144179

Trained immunity driven by Enterococcus faecalis ribosomal protein S11 enhances antigen presentation and boosts influenza vaccine efficacy via nanoparticle delivery.

Jian-Gang Zhang, Cheng-Kai Zhou, Yu Gao, Xiao-Mei Zhang, Ke Ma, Zi-Ran Peng, Xue-Yue Luo, Zhen-Zhen Liu, Xiao-Qi Lin, Wei Chen, Yong-Jun Yang.

  The limited availability of adjuvants poses a significant challenge in modern vaccine development, as they play a crucial role in enhancing vaccine efficacy. Trained immunity, driven by metabolic and epigenetic reprogramming of innate immune cells, offers a novel platform for adjuvant discovery. However, current studies predominantly focus on classical inducers such as β-glucan and BCG, limiting the exploration of key genes underlying trained immune responses. Here, we introduce a phenotypic evaluation model using Galleria mellonella larvae, identifying the gut commensal Enterococcus faecalis as a potent inducer of trained immunity. Through bioactivity-guided fractionation, we identified ribosomal protein S11 (RPS11) as the active agonist. Mechanistically, RPS11 induces trained immunity through TLR4-TET2 signaling-mediated ribosomal biogenesis inhibition, thereby shaping the enhanced MHC molecule expression phenotype in trained antigen-presenting cells. Notably, RPS11 conjugated with superparamagnetic iron oxide nanoparticles (RSNPs) significantly boosted the efficacy of an influenza vaccine. These findings highlight that harnessing the synergistic effects of innate and adaptive immune memory, combined with nanoparticle-based delivery of trained immunity agonists, presents a promising strategy for advancing next-generation vaccines against infectious diseases.

Keywords:  Bioactivity-guided fractionation; Commensal bacteria; Nanoparticle vaccines; Ribosomal biogenesis; Trained immunity

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144179
PLoS One. 2025 ;20(5): e0323376

β-glucan induced trained immunity enhances antibody levels in a vaccination model in mice.

Jainu Ajit, Qing Chen, Trevor Ung, Matthew Rosenberger, Jeremiah Kim, Ani Solanki, Jingjing Shen, Aaron P Esser Kahn.

Trained immunity improves disease resistance by strengthening our first line of defense, the innate immune system. Innate immune cells, predominantly macrophages, are epigenetically and metabolically rewired by β-glucan, a fungal cell wall component, to induce trained immunity. These trained macrophages exhibit increased co-stimulatory marker expression and altered cytokine production. Signaling changes from antigen-presenting cells, including macrophages, polarize T-cell responses. Recent work has shown that trained immunity can generally enhance protection against infection, and some work has shown increased protection with specific vaccines. It has been hypothesized that the trained cells themselves potentially modulate adaptive immunity in the context of vaccines. However, the mechanistic link between trained immunity and subsequent vaccinations to enhance antibody levels has not yet been identified. We report that trained immunity induced by a single dose of β-glucan increased antigen presentation in bone-marrow-derived macrophages (BMDMs) and CD4+ T cell proliferation in-vitro. Mice trained with a single dose of β-glucan a week before vaccination elicited higher antigen-specific antibody levels than untrained mice. Further experiments validate that macrophages mediate this increase. This effect persisted even after vaccinations with 100 times less antigen in trained mice. We report β-glucan training as a novel prophylactic method to enhance the effect of subsequent vaccines.

DOI: https://doi.org/10.1371/journal.pone.0323376
Fish Shellfish Immunol. 2025 May 20. pii: S1050-4648(25)00318-3. [Epub ahead of print]163 110429

Characterization of type 2 interleukin-1 receptor (IL-1R2) as an inhibitory regulator of trained immunity in teleost.

Shu Cui, Qiuxi Yang, Yuanxing Zhang, Qin Liu, Dahai Yang, Zhuang Wang.

  Trained immunity refers to the immune memory of innate immune cells, which is driven by metabolic rewiring and epigenetic reprogramming after initial stimulation. Several endogenous inducers of trained immunity have been reported, such as oxidized low-density lipoprotein (oxLDL), interleukin, and interferon. However, the negative regulatory molecules of trained immunity remain largely elusive. In this study, we identify a member of IL-1 family receptors, interleukin-1 receptor 2 (IL-1R2), as a potential inhibitory regulator of trained immunity in turbot. Pre-incubating recombinant IL-1R2 protein (rIL-1R2) with turbot neutrophils could inhibit β-glucan-induced training phenotypes. Specifically, rIL-1R2 incubation significantly decreases the expression of genes involved in the TLR/IL-1R and downstream MAPK/NF-κB signaling pathway in trained neutrophils, and further reversing the elevated expression of pro-inflammatory cytokines such as IL-6 and TNF-α in response to bacterial reinfection. Moreover, rIL-1R2 inhibits the increasing production of intracellular reactive oxygen (ROS), myeloperoxidase (MPO) activity and neutrophil extracellular traps (NETs) in trained neutrophils, ultimately impairing the bacterial killing ability. Taken together, our work demonstrates that the decoy receptor IL-1R2 could negatively regulate trained immunity activation in turbot neutrophils. These findings enrich the theory of trained immunity in teleost fish and provide a potential target for disease prevention and treatment in aquaculture.

Keywords:  Bactericidal activity; IL-1R2; Neutrophils; Trained immunity; Turbot

DOI:  https://doi.org/10.1016/j.fsi.2025.110429
Biomed Pharmacother. 2025 May 14. pii: S0753-3322(25)00336-1. [Epub ahead of print]188 118142

Macrophage immunometabolism dysregulation and inflammatory disorders.

Karen Pomeyie, Francis Abrokwah, Daniel Boison, Benjamin Amoani, Foster Kyei, Cynthia A Adinortey, Prince Amoah Barnie.

  Macrophages are innate immune cells which are involved in triggering inflammation. Growing evidence shows that, macrophages respond to intracellular and extracellular cues which makes them adopt either anti-inflammatory or pro-inflammatory functions and phenotypes. Immunometabolism has been identified as one of the prominent factors which contributes massively towards the cessation and the development of inflammation as an immune response to infections and autoimmune diseases. However, when inflammation is poorly regulated, it leads to dire consequences. This illustrates that, understanding the role of immunometabolism in the regulation of inflammation, is paramount. In view of this, the review investigated the role of metabolic pathways such as: glycolysis, tricarboxylic acid cycle, pentose phosphate pathway, fatty acid oxidation, amino acid metabolism in macrophage reprogramming. The role of the intermediates and enzymes associated with these metabolic pathways in the regulation of, macrophage reprogramming and polarisation or activation was also reviewed. It was unveiled that, manipulating metabolic intermediates and enzymes could impact cellular immunometabolism. This eventually influences macrophage reprogramming and thus influences the generation of either a pro-inflammatory or anti-inflammatory response.

Keywords:  Immunometabolism; Inflammatory disorders; Macrophage

DOI:  https://doi.org/10.1016/j.biopha.2025.118142
Immunology. 2025 May 21.

BCG Vaccination Reprograms the Function of M-MDSCs and Aggravates Necrotizing Enterocolitis in Neonates.

Yingying Chen, Hui Li, Yongmei Zhang, Fajie Zhao, Jie Zhou.

  Bacillus Calmette-Guérin (BCG), a live-attenuated vaccine primarily used against tuberculosis (TB), also provides protection against a broad array of antigens or heterologous antigens through the induction of trained immunity (TI). While BCG is generally safe for full-term infants, its application in preterm infants is contentious due to their immature immune systems and heightened susceptibility to adverse effects. Preterm infants, particularly those with low birth weight, are at an elevated risk of severe complications, such as necrotizing enterocolitis (NEC), a life-threatening inflammatory condition of the intestines. NEC is characterised by dysregulated immune responses to microbial colonisation, with myeloid-derived suppressor cells (MDSCs) playing a crucial role in maintaining immune tolerance during early life. This study reveals that BCG vaccination significantly exacerbates NEC severity (p = 0.0048) by enhancing glycolysis and upregulating mTOR-HIF1α signalling in neonatal monocytic MDSCs (M-MDSCs), thereby impairing their immunosuppressive function. Pharmacological or genetic inhibition of mTOR-HIF1α signalling or glycolysis pathways restored M-MDSC function and mitigated NEC severity. These findings complement our previous work on BCG's effects on polymorphonuclear (PMN)-MDSCs and highlight the dual role of BCG: while it provides protective benefits in certain contexts, it may also increase NEC risk in preterm infants by disrupting MDSC-mediated immune tolerance. This study offers critical insights into the mechanisms underlying BCG's off-target effects and underscores the necessity of tailored vaccination strategies for preterm infants to minimise potential risks.

Keywords:  bacillus Calmette–Guérin; glycolysis; mTOR‐HIF1α signalling; monocytic myeloid‐derived suppressor cells; necrotizing enterocolitis; rapamycin

DOI:  https://doi.org/10.1111/imm.13946
Infect Immun. 2025 May 19. e0006125

Colonization dynamics of Streptococcus pneumoniae are determined by polymorphisms in the BlpAB transporter.

Surya D Aggarwal, Jacqueline Toussaint, John A Lees, Jeffrey N Weiser.

  Colonization of the human airways, the first step in the pathogenesis of Streptococcus pneumoniae (Spn), is the determining factor in the ecological spread of the bacterium. Since co-colonization by multiple strains is common, within-host bacterial competition contributes to the success of Spn strains. Competition both between and within strains is mediated by bacteriocin gene clusters, notably the quorum sensing-regulated bacteriocin-like peptide (blp) locus. A key component of this system is the BlpAB transporter that exports pheromones and bacteriocins expressed by the blp locus. However, ~75% of Spn strains lack a functional BlpAB transporter and instead rely on the paralogous ComAB transporter for this export, raising questions about the evolutionary persistence of BlpAB(+) strains. Using molecular barcoding, we demonstrate that BlpAB(+) and BlpAB(-) strains show major differences in population dynamics during colonization modeled in mice. The BlpAB(+) strains exhibit slower loss of clonal diversity as a consequence of intrastrain competition relative to their isogenic BlpAB(-). The contribution of a functional BlpAB transporter was then examined in an association study of >2,000 human carriage isolates from a highly colonized population. The median carriage duration was ~177 days longer for BlpAB(+) relative to BlpAB(-) strains. This increased duration of natural carriage correlates with a competitive advantage for BlpAB(+) strains when tested in the murine model. Thus, our work provides insight into how differences in the population dynamics of Spn mediated by bacterial competition impact host colonization.IMPORTANCESpn is a frequent colonizer of the human upper respiratory tract. Success during colonization is dictated by the arsenal of weapons these bacteria possess, which provides them with an advantage over their competitors. A key example includes the blp bacteriocins that are exported by the cell through both BlpAB and ComAB transporters. While most Spn strains lack a functional BlpAB, a subset of the strains retains it. Given this redundancy in export systems, our study questioned the evolutionary advantage of retaining BlpAB. Herein, we show that a functional BlpAB transporter causes a slower loss of clonal diversity in vivo. This correlates with longer Spn carriage duration in the human population and a competitive advantage during experimental co-colonization. Our work highlights the reasons behind the persistence of Spn with a functional BlpAB. These findings reveal how genetic variability in the blp locus shapes Spn colonization and evolutionary success.

Keywords:  bacteriocins; colonization; pneumococcus; population dynamics; quorum sensing

DOI:  https://doi.org/10.1128/iai.00061-25
Microbiome. 2025 May 22. 13(1): 131

Porcine nasal organoids to model interactions between the swine nasal microbiota and the host.

Laura Bonillo-Lopez, Noelia Carmona-Vicente, Ferran Tarrés-Freixas, Karl Kochanowski, Jorge Martínez, Mònica Perez, Marina Sibila, Florencia Correa-Fiz, Virginia Aragon.

   BACKGROUND: Interactions between the nasal epithelium, commensal nasal microbiota, and respiratory pathogens play a key role in respiratory infections. Currently, there is a lack of experimental models to study such interactions under defined in vitro conditions. Here, we developed a porcine nasal organoid (PNO) system from nasal tissue of pigs as well as from cytological brushes.
RESULTS: PNOs exhibited similar structure and cell types to the nasal mucosa, as evaluated by immunostaining. PNOs were inoculated with porcine commensal strains of Moraxella pluranimalium, Rothia nasimurium, and the pathobiont Glaesserella parasuis for examining host-commensal-pathogen interactions. All strains adhered to the PNOs, although at different levels. M. pluranimalium and G. parasuis strains stimulated the production of proinflammatory cytokines, whereas R. nasimurium induced the production of IFNγ and diminished the proinflammatory effect of the other strains.
CONCLUSIONS: Overall, PNOs mimic the in vivo nasal mucosa and can be useful to perform host-microbe interaction studies. Video Abstract.

Keywords:  Airway organoid models; Host-microbe interactions; Microbial interactions; Nasal microbiota; Porcine nasal organoids

DOI:  https://doi.org/10.1186/s40168-025-02088-9
Nat Immunol. 2025 May 19.

Antibiotics, microbiota and the calibration of infant vaccine responses.

Yupeng Feng, Bali Pulendran.

DOI: https://doi.org/10.1038/s41590-025-02169-9
Mol Immunol. 2025 May 21. pii: S0161-5890(25)00129-4. [Epub ahead of print]183 213-224

NLRP3 regulates macrophage function by M-CSF/M-CSFR signaling in acute radiation-induced lung injury.

Yuqing Feng, Jiao Kong, Wanyue Sun, Yan Li, Fule Ren, Xuetong Sun, Mingxi Li, Ying Liu, Shilong Sun, Haiyan Qin.

  Alveolar macrophages are the most abundant macrophages in the healthy lungs and are important players in maintaining lung homeostasis as well as orchestrating tissue repair after injury. Many studies have proved that the initiation, development and progression of acute radiation-induced lung injury are associated with alveolar macrophages. However, lung-associated macrophages function and developmental processes in acute radiation-reduced lung injury remain elusive. To investigate the role of NLRP3 in radiation-reduced lung injury, we established wild-type and NLRP3-/- mice models, and we found that the extent of pneumonia reduced in NLRP3-/- IR group. In in vivo experiments, we observed a decrease in the number of macrophages in NLRP3-/- group. At the same time, in in vitro experiments we have found that macrophages are more easily polarized toward the M2 after radiation in NLRP3-/- group compared with the control group. Our findings reveal that NLRP3 affects the differentiation and chemotaxis of alveolar macrophages through M-CSF/M-CSFR signalling at the onset of radiation-induced lung injury.

Keywords:  Alveolar macrophages; M-CSF/M-CSFR; NLRP3; Radiation-induced lung injury

DOI:  https://doi.org/10.1016/j.molimm.2025.05.009
J Reprod Immunol. 2025 May 16. pii: S0165-0378(25)00120-2. [Epub ahead of print]170 104542

Impact of the maternal microbiome on neonatal immune development.

Eleni Dubé-Zinatelli, Edwige Mayotte, Luna Cappelletti, Nafissa Ismail.

  Historically, multigenerational health and disease transmission have primarily focused on genetic inheritance. However, the discovery that beneficial microorganisms known as commensal microbiota outnumber human genes tenfold has reshaped this perspective, highlighting their critical role in maintaining homeostasis and protecting against pathogens. Unlike the human genome, commensal microbiota is not genetically inherited but is acquired anew with each generation. with initial gut colonization playing a pivotal role in shaping an infant's immune system, neurodevelopment, and long-term health, all heavily influenced by maternal factors. In this review, we examine emerging research on maternal microbial influences on the fetus beginning in utero. We provide an updated overview of the current insights into the impact of the vaginal microbiome during parturition on offspring immunity and discuss the potential long-term health implications for infants born via cesarean section. We explore the advantages and limitations of techniques designed to mitigate these effects, such as vaginal seeding and emphasize that the development of the neonatal immune system is a dynamic process influenced by maternal factors beyond birth, including the transfer of microbiota through breast milk and skin contact. Finally, we present gaps in current research and propose future research directions to deepen our understanding of the impacts of the maternal microbiome on her child. Together, these insights demonstrate how maternal influence on offspring health and immunity extends beyond genetic factors, encompassing the transmission of microbiota, which, in turn, has profound long-term implications for health and disease resilience, offering a novel perspective on intergenerational health dynamics.

Keywords:  Breast milk; Cesarian section; Gut-brain-axis; Microbiota; Skin-to-skin contact; Vaginal birth; Vaginal seeding

DOI:  https://doi.org/10.1016/j.jri.2025.104542
J Leukoc Biol. 2025 May 22. pii: qiaf071. [Epub ahead of print]

Microenvironmental Conditions and Serum Availability Alter Primary Human Macrophage NF-κB Inflammatory Response and Function.

Breana Channer, Marzieh Daniali, Lexi Sheldon, Katy Emanuel, Yash Agarwal, Taylor Kist, Brian J Murphy, Meng Niu, Will Dampier, Howard Fox, Peter J Gaskill.

  Macrophages are central to innate immunity and are routinely used in vitro to examine molecular mechanisms contributing to innate immune signaling. However, there is a lack of consensus within the field for optimal in vitro culturing methods, and it is not well understood whether differences in culture conditions produce incongruent outcomes. Here, we compared the effects of commonly used culture medium compositions on TLR4-mediated pro-inflammatory activity in primary human monocyte-derived macrophages (hMDM) isolated from healthy blood donors. hMDM were cultured in fetal bovine serum (FBS)-containing or FBS-free conditions in either DMEM, RPMI, or in Macrophage-Serum Free Medium (M-SFM). LPS-mediated immune response was measured through NF-κB activation and cytokine and chemokine secretion, which were muted in M-SFM cultures compared to DMEM and RPMI cultures. FBS supplementation increased total cytokine secretion in response to LPS but also showed higher baseline secretion, suggesting a pro-inflammatory phenotype. Moreover, M-SFM cultures exhibited less phagocytosis compared to DMEM and RPMI cultures. Morphologic analysis of unstimulated hMDM revealed the highest cell area and length-to-width ratio in M-SFM compared to DMEM or RPMI cultures. FBS-free and M-SFM conditions produced distinct transcriptional profiles compared to media supplemented with FBS, most notably in cell cycle pathways and lipid homeostasis, respectively. Overall, DMEM and RPMI produce comparable morphologic and functional results, albeit with some small differences, while M-SFM produces a muted inflammatory response in macrophages. These data demonstrate that in vitro microenvironment drives differential inflammatory outcomes in human macrophages and is a critical component of experimental design in this cell type.

Keywords:  Macrophage; NF-kB; TLR4; culture media; inflammation; innate immunity; morphology; myeloid cells; serum

DOI:  https://doi.org/10.1093/jleuko/qiaf071
Nat Microbiol. 2025 May 21.

Iron at the crossroads of host-microbiome interactions in health and disease.

Garam Choi, Nicholas J Bessman.

Iron is an essential dietary micronutrient for both humans and microorganisms. Disruption of iron homeostasis is closely linked, as both a cause and an effect, to the development and progression of gut microbiota dysbiosis and multiple diseases. Iron absorption in humans is impacted by diverse environmental factors, including diet, medication and microbiota-derived molecules. Accordingly, treatment outcomes for iron-associated diseases may depend on an individual patient's microbiome. Here we describe various iron acquisition strategies used by the host, commensal microorganisms and pathogens to benefit or outcompete each other in the complex gut environment. We further explore recently discovered microbial species and metabolites modulating host iron absorption, which represent potential effectors of disease and therapeutic targets. Finally, we discuss the need for mechanistic studies on iron-host-microbiome interactions that can affect disease and treatment outcomes, with the ultimate aim of supporting the development of microbiome-based personalized medicine.

DOI: https://doi.org/10.1038/s41564-025-02001-y
Adv Sci (Weinh). 2025 May 23. e00582

Hosts and Commensal Bacteria Synergistically Antagonize Opportunistic Pathogens at the Single-Cell Resolution.

Sheng Zhang, Ziguang Wang, Anqi Liu, Jinshu Li, Jingjing Zhuang, Xiaowen Ji, Paul I Mulama, Maoye Li, Haiqun Cao, Eng-King Tan, Wei Liu.

  Natural microbes coexist in a diverse species population with competition for space and nutrient resources. However, the molecular mechanisms underpinning the regulatory networks of microbes among themselves and with their host are still in infancy. Here, it is reported that Drosophila and the commensal Lactiplantibacillus plantarum form an alliance to compete with the pathogenic Serratia marcescens using the integrated three-species model system. In the dual-species model, larvae diminish the L. plantarum population, but reversibly increase lactate production through altering its transcriptional reprogramming. In the tripartite-species model, larvae facilitate the growth of L. plantarum that confers colonization resistance against S. marcescens. On the other hand, S. marcescens launches sophisticated arms race strategies to impair colonization resistance by sensing lactate derived from L. plantarum. More importantly, the S. marcescens population challenged with Drosophila and L. plantarum adaptively diverge into virulent and reduced virulence subclusters with an increase in resistance heterogeneity. To form the alliance with Drosophila, heterogeneity in lactate generation is broadened among L. plantarum subpopulations. Altogether, these findings provide an insight into the host-commensal-pathogen symbiosis at both bulk and single-cell resolutions, advancing fundamental concepts of precise manipulation of bacterial communities.

Keywords:  bacterial single‐cell RNA‐seq; heterogeneity; metabolic adaptations; pathogenicity

DOI:  https://doi.org/10.1002/advs.202500582
Biomed J. 2025 May 21. pii: S2319-4170(25)00046-0. [Epub ahead of print] 100872

The clockwork macrophage: timing in innate immunity.

Siyu Chen, Nick Ciccone, David Ray.

  The circadian clock enables organisms to predict daily environmental changes and synchronize their physiology and behaviour accordingly. Macrophages, key sensor cells in the innate immune system, exhibit cell-autonomous circadian rhythmicity. This circadian rhythmic behaviour is synchronised to the central clock in the hypothalamus as a result of neural, and hormonal signals. Macrophage rhythms and responses involve sensing temporal cues, integrating information from tissue-specific environments, and initiating context-appropriate, time-gated responses. On a broader scale, monocytes and macrophages communicate and synchronize with other immune cells, migrate throughout the body, and infiltrate tissues, collectively contributing to circadian regulation in both health and disease. While the field of macrophage circadian biology is rapidly advancing, it is equally important to reflect on its historical development, which has been shaped by over two centuries of accumulating knowledge and technological progress. This review traces key milestones in macrophage and circadian research, examining how recent discoveries have refined our understanding of early foundational questions and setting the stage for future inquiries. Notably, many intriguing questions remain unresolved, including the circadian regulation of macrophage function under steady-state conditions, the tissue-specific heterogeneity of macrophage circadian rhythms, and the role of macrophage circadian clocks in disease pathogenesis and their potential clinical implications.

Keywords:  Macrophage; circadian rhythm; immune response; metabolism

DOI:  https://doi.org/10.1016/j.bj.2025.100872
J Nanobiotechnology. 2025 May 16. 23(1): 349

The biological activity and potential of probiotics-derived extracellular vesicles as postbiotics in modulating microbiota-host communication.

Xiaoming Zhang, Ye Wang, Qiyu E, Muhammad Naveed, Xiuli Wang, Yinhui Liu, Ming Li.

  Probiotics such as Lactobacillus and Bifidobacterium spp. have been shown to be critical for maintaining host homeostasis. In recent years, key compounds of postbiotics derived from probiotic metabolism and cellular secretion have been identified for their role in maintaining organ immunity and regulating intestinal inflammation. In particular, probiotic-derived extracellular vesicles (PEVs) can act as postbiotics, maintaining almost the same functional activity as probiotics. They also have strong biocompatibility and loading capacity to carry exogenous or parental active molecules to reach distal organs to play their roles. This provides a new direction for understanding the intrinsic microbiota-host communication mechanism. However, most current studies on PEVs are limited to their functional effects/benefits, and their specific physicochemical properties, composition, intrinsic mechanisms for maintaining host homeostasis, and possible threats remain to be explored. Here, we review and summarize the unique physicochemical properties of PEVs and their bioactivities and mechanisms in mediating microbiota-host communication, and elucidate the limitations of the current research on PEVs and their potential application as postbiotics.

Keywords:  Extracellular vesicles (EVs); Host homeostasis; Microbiota-host communication; Postbiotics; Probiotic-derived extracellular vesicles (PEVs)

DOI:  https://doi.org/10.1186/s12951-025-03435-6
J Inflamm (Lond). 2025 May 19. 22(1): 19

Exosomes derived from M2 macrophages regulate airway inflammation by modulating epithelial cell proliferation and apoptosis.

Yinying Ren, Mi Zhou, Yuehan Li, Yan Li, JinYing Xiang, Fang Deng, Zhengxiu Luo, Enmei Liu, Jinyue Yu, Zhou Fu, Fengxia Ding, Bo Liu.

   BACKGROUND: Asthma is a chronic inflammatory disease characterized by airway remodeling and immune dysregulation. This study aimed to explore the mechanisms by which M2 macrophage-derived exosomes (M2Φ-Exos) regulate airway inflammation in asthma by modulating epithelial cell proliferation and apoptosis.
METHODS: M2Φ-Exos were extracted and characterized by morphology, size, and marker protein expression. In vitro, the effects of M2Φ-Exos on House Dust Mites (HDM)-stimulated mouse lung epithelial cells (MLE-12s) were evaluated using western blotting to analyze Proliferating Cell Nuclear Antigen (PCNA), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved caspase-3 expression. In vivo, M2Φ-Exos were administered to HDM-induced asthmatic mice to assess their impact on airway inflammation, epithelial remodeling, and proliferation-apoptosis balance using immunohistochemistry, immunofluorescence, and western blotting. Cytokine levels in lung tissue and bronchoalveolar lavage fluid (BALF) were measured by qRT-PCR and ELISA.
RESULTS: M2Φ-Exos displayed typical cup-shaped morphology, an average diameter of 115.5 nm, and expressed marker proteins CD9, TSG101, and CD63. MLE-12 cells internalized M2Φ-Exos, leading to reduced abnormal proliferation and apoptosis in HDM-stimulated cells. In asthmatic mice, M2Φ-Exos alleviated airway inflammation and epithelial thickening while reducing PCNA, cleaved caspase-3, and Bax levels and increasing Bcl-2 expression. M2Φ-Exos suppressed pro-inflammatory cytokines (IL-4, IL-5, IL-13) and Transforming growth factor (TGF)-β, while enhancing anti-inflammatory cytokine IFN-γ and IL-10.
CONCLUSION: These findings demonstrate that M2Φ-Exos regulate the imbalance in epithelial proliferation and apoptosis in asthma, reducing inflammation and mitigating tissue remodeling, and provide new insights into potential therapeutic strategies for asthma management.

Keywords:  Apoptosis; Asthma; Exosome; M2 macrophage; Proliferation

DOI:  https://doi.org/10.1186/s12950-025-00444-y
Int Immunopharmacol. 2025 May 20. pii: S1567-5769(25)00871-9. [Epub ahead of print]159 114881

Probiotic DNA epigenetically upregulates epithelial PD-L1 via KDM5A-mediated demethylation to suppress airway allergy by inducing activated Th2 cell apoptosis.

Yan Feng, Ruien Chen, Yixuan Dong, Haiyang Han, Bailing Xie, Lihua Mo, Hui Huangfu, Gui Yang, Yu Liu, Pingchang Yang.

  Current therapies for airway allergy (AA) exhibit limited efficacy in targeting pathogenic Th2-driven inflammation. Probiotics demonstrate immunoregulatory potential, yet the epigenetic mechanisms by which probiotic-derived DNA modulates allergic responses remain unexplored. This study investigates whether Lactobacillus rhamnosus GG DNA (LgDNA) alleviates AA through PD-L1-mediated T cell suppression. A murine AA model was established using house dust mite (Derf2) sensitization and challenge. LgDNA was intranasally administered at 10 μg/mouse/day. Epithelial PD-L1 expression was quantified by flow cytometry and qRT-PCR. KDM5A recruitment and Pd-l1 promoter methylation were analyzed via ChIP-qPCR and bisulfite sequencing. Th2 cell apoptosis was assessed by annexin V/PI staining. LgDNA treatment increased airway epithelial PD-L1 expression by 2.8-fold (P < 0.01) and reduced Derf2-induced Th2 cytokine levels (IL-4: 62 %↓; IL-5: 68 %↓). Mechanistically, LgDNA induced Pd-l1 promoter demethylation (methylation rate: 35 % vs. 78 % in controls) via KDM5A-mediated H3K4me3 modification. KDM5A knockdown abrogated LgDNA-driven PD-L1 upregulation (ΔPD-L1: 1.2-fold vs. 3.1-fold, P < 0.05). PD-L1 overexpression in epithelial cells triggered activated Th2 cell apoptosis (annexin V+PI+: 41 % vs. 12 %), reducing airway hyperresponsiveness by 54 % in AA mice. In summary, LgDNA alleviates AA by epigenetically enhancing epithelial PD-L1 via KDM5A, which induces pathogenic Th2 cell apoptosis. This study identifies a novel probiotic DNA-based epigenetic axis for allergic disease therapy, bridging microbiome biology with immune checkpoint regulation.

Keywords:  Airway allergy; Epigenetic regulation; KDM5A; PD-L1; Probiotic DNA; Th2 cell apoptosis

DOI:  https://doi.org/10.1016/j.intimp.2025.114881
Cell Immunol. 2025 May 13. pii: S0008-8749(25)00057-7. [Epub ahead of print]413 104972

Integrated proteomics and phosphoproteomics profiling dynamic signaling networks underlying two distinct types of macrophage activation.

Lihong Wu, Hang Xu, Xiaonan Zhang, Minghui Zhang, Yuting Xu, Qianyue Zhang, Huiying Tao, Changming Dong, Xinxin Zhang, Mingming Zhou, Jinbo Yang, Chunhua Lin, Qiaoling Song.

  Macrophages play a crucial role in antimicrobial host defense and those with differential maturation/differentiation status differ in inflammatory responses. Herein, GM-CSF and M-CSF primed mouse bone marrow derived macrophages (GM-BMDMs, GM and M-BMDMs, M), the well-established macrophage models in vitro, were utilized and their dynamic signaling changes in response to gram-negative bacteria component LPS treatment were analyzed using both 4D label-free proteomics and phosphoproteomics. Protein changes maintained relatively constant within or across GM and M macrophages post LPS challenge while phospho-protein exhibited more diverse and transient changes. Early induction of phospho-mediated GTPase activities, mRNA processing, and protein-mediated metabolic changes like oxidative phosphorylation (OXPHOS)/mitochondria function was identified at 1 h and maintained until 6 h post LPS treatment in GM and M while canonical TLR mediated MyD88-dependent and -independent pathways were activated at 3 and 6 h, individually at protein levels. Classical and novel phospho-sites for MyD88 and TRIF signaling pathways were also detected by phosphoproteomics. Comprehensively, the integrated protein and phospho-protein trend analysis was conducted and the core protein-phospho-protein network for the early phase actin reorganization, phagocytosis, and TLR signaling in both GM and M were presented. Taken together, these data described differences and similarities between these two types of macrophages in terms of their inflammatory responses to LPS.

Keywords:  GM-CSF; LPS challenge; M-CSF; Macrophage; Phosphoproteomics; Proteomics

DOI:  https://doi.org/10.1016/j.cellimm.2025.104972