bims-traimu 2025-02-09 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–02–09
ten papers selected by
Yantong Wan, Southern Medical University

Innate Immune Memory is Stimulus Specific.
Trained immunity in chronic inflammatory diseases and cancer.
Early life psychosocial stress increases binge-like ethanol consumption and CSF1R inhibition prevents stress-induced alterations in microglia and brain macrophage population density.
Induction of endotoxin tolerance in murine monocyte and macrophage cell populations - optimal LPS dose and compartment-specific reversal by β-glucan.
Author Correction: β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus.
IRG1/itaconate enhances efferocytosis by activating Nrf2-TIM4 signaling pathway to alleviate con A induced autoimmune liver injury.
Molecular control of PDPNhi macrophage subset induction by ADAP as a host defense in sepsis.
Ficolin A and ficolin B aggravate poly(I:C) secondary LPS stimulation-induced acute lung injury by modulating alveolar and interstitial macrophages.
Tolerance during infection.
Dynamic proteome and phosphoproteome profiling reveals regulatory mechanisms in LPS-stimulated macrophage inflammatory responses.

bioRxiv. 2025 Jan 24. pii: 2025.01.22.634275. [Epub ahead of print]

Innate Immune Memory is Stimulus Specific.

Aoife O'Farrell, Zijian Niu, Jingxin Li, Laura C Van Eyndhoven, Kavitha Sarma, Arjun Raj.

Innate immune memory (also termed trained immunity) is defined in part by its ability to cross-protect against heterologous pathogens, and can be generated by many different stimuli, suggesting a "universal" trained state. However, different stimuli could form distinct memories, leading to stimulus-specific trained responses. Here, we use primary human monocyte-derived macrophages to demonstrate phenotypic and epigenetic stimulus specificity of innate immune memory six days after initial exposure. Quantification of cytokine production with single-molecule RNA imaging demonstrates stimulus-specific patterns of response to restimulation at the single cell level. Differential licensing of inflammatory transcription factors is associated with encoding of specificities in chromatin. Trained cells show stronger responses to secondary stimuli that are more similar to the initial stimulus they experienced, suggesting a functional role for these stimulus-specific memories. Rather than activating a universal training state, our findings demonstrate that different stimuli impart specific memories that generate distinct training phenotypes in macrophages.

DOI: https://doi.org/10.1101/2025.01.22.634275
Nat Rev Immunol. 2025 Jan 31.

Trained immunity in chronic inflammatory diseases and cancer.

George Hajishengallis, Mihai G Netea, Triantafyllos Chavakis.

A decade after the term 'trained immunity' (TRIM) was coined to reflect the long-lasting hyper-responsiveness of innate immune cells with an epigenetically imprinted 'memory' of earlier stimuli, our understanding has broadened to include the potential implications of TRIM in health and disease. Here, after summarizing the well-documented beneficial effects of TRIM against infections, we discuss emerging evidence that TRIM is also a major underlying mechanism in chronic inflammation-related disorders such as periodontitis, rheumatoid arthritis and cardiovascular disease. Furthermore, mounting evidence indicates that the induction of TRIM by certain agonists confers protective antitumour responses. Although the mechanisms underlying TRIM require further study, the current knowledge enables the experimental development of innovative therapeutic approaches to stimulate or inhibit TRIM in a context-appropriate manner, such as the stimulation of TRIM in cancer or its inhibition in inflammatory disorders.

DOI: https://doi.org/10.1038/s41577-025-01132-x
Brain Behav Immun Health. 2025 Feb;43 100933

Early life psychosocial stress increases binge-like ethanol consumption and CSF1R inhibition prevents stress-induced alterations in microglia and brain macrophage population density.

Stephen C Gironda, Samuel W Centanni, Jeffrey L Weiner.

  Early life stress (ELS) has lasting consequences on microglia and brain macrophage function. During ELS, microglia and brain macrophages alter their engagement with synapses leading to changes in neuronal excitability. Further, ELS can induce innate immune memory formation in microglia and brain macrophages resulting in altered responsivity to future environmental stimuli. These alterations can result in lasting adaptations in circuit function and may mediate the relationship between ELS and the risk to develop alcohol use disorder (AUD). Whether microglia and brain macrophages truly mediate this relationship remains elusive. Here, we report: 1) an ELS model, psychosocial stress (PSS), increases binge-like ethanol consumption in early adulthood. 2) Repeated binge-like ethanol consumption increases microglia and brain macrophage population densities across the brain. 3) PSS may elicit innate immune memory formation in microglia and brain macrophages leading to altered population densities following repeated binge-like ethanol consumption. 4) Microglia and brain macrophage inhibition trended towards preventing PSS-evoked changes in binge-like ethanol consumption and normalized microglia and brain macrophage population densities. Therefore, our study suggests that acutely inhibiting microglia and brain macrophage function during periods of early life PSS may prevent innate immune memory formation and assist in reducing the risk to develop AUD.

Keywords:  Alcohol; CSF1R inhibition; Early life stress; Light-Sheet Fluorescence Microscopy; Macrophage; Microglia

DOI:  https://doi.org/10.1016/j.bbih.2024.100933
Food Funct. 2025 Feb 07.

Induction of endotoxin tolerance in murine monocyte and macrophage cell populations - optimal LPS dose and compartment-specific reversal by β-glucan.

Bart G J Moerings, Coen Govers, Jeroen van Bergenhenegouwen, Jurriaan J Mes, Miriam van Dijk, Renger F Witkamp, Klaske van Norren, Suzanne Abbring.

Beta-glucans, naturally present in foods like wheat, mushrooms, and yeast, have shown potential in reversing immunosuppression. However, the existing evidence solely relies on ex vivo studies assessing direct effects of β-glucans on macrophages. To investigate whether such effects also occur after their oral administration, this study first systematically examined the immunosuppressive effects of LPS in mice. Subsequently, we assessed the ability of yeast-derived whole β-glucan particles (yWGP), administered through the diet, to counteract LPS-induced immunological tolerance. Immunosuppression following intraperitoneal administration of 20, 200, or 2000 μg kg-1 LPS was demonstrated by reduced TNF-α and IL-6 release upon ex vivo LPS stimulation of immune cells harvested from the peritoneal fluid, spleen, and bone marrow. Immunosuppression in blood was detected only after 200 and 2000 μg kg-1 LPS. LPS tolerance extended to heterologous stimuli (PAM3Cys, heat-killed Pseudomonas aeruginosa), indicating cross-tolerance. Due to animal discomfort at 2000 μg kg-1 LPS, as evidenced by a significantly enhanced clinical severity score, a dose of 200 μg kg-1 LPS was selected for the follow-up trial. In this experiment, mice fed a yWGP-supplemented diet for two weeks prior to LPS administration showed effective reversal of LPS tolerance, reflected by restored TNF-α levels in peritoneal cells but not in other monocyte- and macrophage-containing cell populations. Together, these studies demonstrate that peritoneal administration of 200 μg kg-1 LPS induced ex vivo LPS tolerance in all immunological organs studied, without significantly compromising animal welfare. The selective efficacy of dietary β-glucans to counteract immunosuppression, which is often observed in vulnerable and immunocompromised patient populations, warrants further clinical evaluation.

DOI: https://doi.org/10.1039/d4fo05223d
Nat Immunol. 2025 Feb 07.

Author Correction: β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus.

Nargis Khan, Kim A Tran, Raphael Chevre, Veronica Locher, Mathis Richter, Sarah Sun, Mina Sadeghi, Erwan Pernet, Andrea Herrero-Cervera, Alexandre Grant, Ahmed Saif, Jeffrey Downey, Eva Kaufmann, Shabaana Abdul Khader, Philippe Joubert, Luis B Barreiro, Bryan G Yipp, Oliver Soehnlein, Maziar Divangahi.

DOI: https://doi.org/10.1038/s41590-025-02099-6
Cell Commun Signal. 2025 Feb 05. 23(1): 63

IRG1/itaconate enhances efferocytosis by activating Nrf2-TIM4 signaling pathway to alleviate con A induced autoimmune liver injury.

Liwu Zeng, Yaxin Wang, Yongzhou Huang, Wenchang Yang, Pei Zhou, Yaqi Wan, Kaixiong Tao, Ruidong Li.

  Immune response gene 1 (IRG1) is highly expressed in mitochondria of macrophages in a pro-inflammatory state. IRG1 and its metabolites play important roles in infection, immune-related diseases and tumor progression by exerting resistance of pathogens, attenuating inflammation and producing antioxidant substances through various pathways and mechanisms. IRG1 deficiency aggravates liver injury. Efferocytosis is a vital mechanism for preventing the progression of inflammatory tissue damage. However, the mechanism by how IRG1/itaconate regulates efferocytosis in autoimmune hepatitis has yet to be fully understood. Therefore, we explored the influence of IRG1-/- on efferocytosis and its effects on regulating the nuclear factor erythroid 2-associated factor 2 (Nrf2)-T-cell immunoglobulin domain and mucin domain 4 (TIM4) pathway and autoimmune liver injury. An autoimmune hepatitis model was established by injecting Con A into wild-type and IRG1-/- mice via the tail vein. Liver injury and inflammatory response were assessed. The efferocytosis role of IRG1-/- macrophages and its potential regulatory mechanisms were also analysed. Exogenous 4-octyl itaconate (OI) supplementation promoted the expression of Nrf2 and TIM4 and restored IRG1-/- bone marrow-derived macrophage (BMDM) efferocytosis, whereas inhibition of Nrf2 mediated by ML385 led to impaired efferocytosis of BMDMs, decreased expression of TIM4, and aggravated liver inflammation injury. Additionally, after supplementing Nrf2-/- BMDMs with exogenous OI, we evaluated the changes in its efferocytosis effect, efferocytosis did not change, and the protective effect of OI disappeared. However, when TIM4 was blocked, the efferocytotic effect of BMDMs was attenuated, inflammatory liver injury and oxidative stress were aggravated. OI promoted the transformation of macrophages into M2 macrophages, and this was inhibited when TIM4 was blocked. To our best understanding, this is the initial exploration to show that TIM4, a downstream molecule of the IRG1/itaconate-Nrf2 pathway, regulates macrophage efferocytosis. These findings suggest a new mechanism and potential treatment for promoting the resolution of inflammation and efferocytosis in autoimmune hepatitis.

Keywords:  Autoimmune hepatitis; Efferocytosis; Itaconate; TIM4

DOI:  https://doi.org/10.1186/s12964-025-02075-5
JCI Insight. 2025 Feb 04. pii: e186456. [Epub ahead of print]

Molecular control of PDPNhi macrophage subset induction by ADAP as a host defense in sepsis.

Pengchao Zhang, Xinning Wang, Xiaodong Yang, Hebin Liu.

  Induction of podoplanin (PDPN) expression is a critical response of macrophages to LPS stimulation or bacterial infection in sepsis, but how this key process of TLR4-stimulated PDPN upregulation is regulated and the impact of PDPN expression on macrophage function remain elusive. Here, we determined how this process is regulated in vitro and in vivo. PDPN failed to be upregulated in TLR4 stimulated macrophages deficient in adhesion and degranulation-promoting adapter protein (ADAP), which could be rescued by the reconstitution of ADAP. A distinct PDPNhi peritoneal macrophage (PM) subset, which exhibited an M2-like phenotype and enhanced phagocytic activity, was generated in WT but not in ADAP-deficient septic mice. The blockade of PDPNhi PMs mimicked the effect of ADAP deficiency, which exacerbated sepsis. Mechanistically, BTK-mediated ADAP Y571 phosphorylation worked together with mTOR to converge on STAT3 activation for the transactivation of the PDPN promoter. Moreover, agonist activation of STAT3 profoundly potentiated the PDPNhi PM subset generation and alleviated sepsis severity in mice. Together, our findings reveal a mechanism whereby ADAP resets macrophage function by controlling the TLR4-induced upregulation of PDPN as a host innate immune defense during sepsis.

Keywords:  Bacterial infections; Immunology; Inflammation; Macrophages; Signal transduction

DOI:  https://doi.org/10.1172/jci.insight.186456
Cytokine. 2025 Jan 31. pii: S1043-4666(25)00015-8. [Epub ahead of print]188 156868

Ficolin A and ficolin B aggravate poly(I:C) secondary LPS stimulation-induced acute lung injury by modulating alveolar and interstitial macrophages.

Ziqi Hu, Xu Wu, Duoduo Yao, Jianhua Liu, Qingli Kong, Yu-Jie Zhou, Xulong Zhang.

  Respiratory viral infection, represented by influenza virus, is easily followed by bacterial infection, the main cause of death. Clinical studies have shown that even mild influenza virus infection followed by secondary bacterial infection can mediate severe pneumonia and lung injury. In this study, mice were intranasally stimulated by polyinosinic-polycytidylic acid [poly(I:C)] followed by lipopolysaccharide (LPS) to simulate respiratory RNA virus secondary Gram-negative bacterial infection. The results demonstrated that poly(I:C) followed by LPS stimulation induced more weight loss, worse lung pathological injury, additional recruitment of neutrophils and interstitial macrophages, and elevated expression of ficolin A/B in the lung neutrophils, alveolar and interstitial macrophages. Knockout of ficolin A/B alleviated the body weight loss, the lung pathological injury, and the pulmonary inflammatory score. Mechanically, knockout of ficolin A/B was associated with reduced interstitial macrophage recruitment and alveolar macrophage exhaustion. These results suggest that ficolin A/B is a potential therapeutic target for severe pneumonia induced by respiratory RNA virus secondary Gram-negative bacterial infection.

Keywords:  Acute lung injury; Ficolin; Innate immune; Lipopolysaccharide (LPS); Polyinosinic-polycytidylic acid [poly(I:C)]

DOI:  https://doi.org/10.1016/j.cyto.2025.156868
Nat Immunol. 2025 Feb;26(2): 149

Tolerance during infection.

Stephanie Houston.

DOI: https://doi.org/10.1038/s41590-025-02083-0
Biochem Biophys Res Commun. 2025 Jan 22. pii: S0006-291X(25)00055-5. [Epub ahead of print]750 151341

Dynamic proteome and phosphoproteome profiling reveals regulatory mechanisms in LPS-stimulated macrophage inflammatory responses.

Chenyang Huang, Yuying Liang, Aolin Jiang, Li Chen, Chang Sun, Dongrong Luo, Zhaofan Xia, Lei Li, Yong Jiang.

  Macrophage-mediated acute inflammation is crucial for pathogen clearance and tissue repair, yet the underlying molecular mechanisms remain inadequately understood. The present study focused on the dynamic profiles of the proteome and phosphoproteome of macrophages exposed to lipopolysaccharide within 1 h. Gene Set Enrichment Analysis (GSEA) identified significantly enriched pathways in fatty acid metabolism and translation during the early inflammatory phase. Further trend analysis of the differentially expressed proteins revealed patterns associated with translation regulation such as translation initiation. Importantly, the nascent chain experiment demonstrated no significant changes in overall gene translation levels during this phase. These data indicate that macrophages maintain intracellular protein homeostasis through translational regulation, with post-translational modifications (PTMs) playing a crucial role in the rapid cellular response to pathogen invasion. Phosphorylation is a key PTM that regulates protein functions in almost all cellular processes. Time-resolved phosphoproteome analysis identified 367 differentially expressed phosphopeptides involved in immune-related pathways that resist infection. Additionally, weighted gene co-expression network analysis (WGCNA) discovered core modules that regulate translation-related processes such as RNA export from nucleus. Moreover, conjoint analysis of the proteome and phosphoproteome identified the hub protein EF1B that exhibited the largest fold change and is also involved in translation. Our data not only provide a more comprehensive understanding of the dynamic molecular networks of acute macrophage inflammation but also provide a systematic proteomic resource for further studies.

Keywords:  Inflammation; Lipopolysaccharide; Macrophage; Phosphoproteomics; Proteomics; Translation regulation

DOI:  https://doi.org/10.1016/j.bbrc.2025.151341