bims-traimu Biomed News
on Trained immunity
Issue of 2026–01–11
eleven papers selected by
Yantong Wan, Southern Medical University
  1. BCG and β-glucan primed monocytes yield dendritic cells that hamper the induction of pro-inflammatory T cell immunity.
  2. Trained immunity links cardiovascular disease and COVID-19.
  3. Immunomodulation by bacterial products promotes innate signatures favorable to macrophage responses in tuberculosis infection.
  4. Biodegradable microparticles promote anti-inflammatory innate immune memory though a size- and mTOR dependent process.
  5. Trained Immunity and Cardiovascular Risk: An Immunological Perspective.
  6. ERK/Smurf1 regulates non-canonical pyroptosis by prompting Caspase-11 ubiquitination.
  7. Molecular Mechanisms of Priming Innate Immunity by Small Extracellular Vesicles Released during Infection with Gram-negative Bacteria.
  8. Trained ILC2 prevent IL-17-associated lung injury during helminth infection through a serotonin-dependent mechanism.
  9. Macrophage glycine transporter supports IL-1β production by modulating the AKT1/mTOR/NLRP3 pathway.
  10. Neonatal lipopolysaccharide administration causes long-term changes in mouse immunosteroids.
  11. Thermotolerance induced by non-lethal heat shock at 40 °C is activated by mitochondrial ROS and is Nrf2-dependent.
  1. Cell Immunol. 2025 Dec 27. pii: S0008-8749(25)00146-7. [Epub ahead of print]419 105060
    BCG and β-glucan primed monocytes yield dendritic cells that hamper the induction of pro-inflammatory T cell immunity.
    Jorge Cuenca-Escalona, Robbin Kramer, Clara Marjalizo-Jimenez, Jorge Domínguez-Andrés, Mihai G Netea, Georgina Flórez-Grau, I Jolanda M de Vries, Sophie K Horrevorts.
      Dendritic cells (DCs) are professional antigen-presenting cells that regulate inflammatory and tolerogenic immunity. Their role within trained immunity, a process in which innate immune cells exhibit memory-like characteristics, remains to be elucidated. To date, increasing evidence indicates that trained immunity underlies the enhanced innate immune response induced by the Bacillus Calmette-Guérin (BCG) vaccine and the fungal cell wall component β-glucan (β-Glc), contributing to protection against heterologous infections and cancer. Concurrently, preclinical evidence suggests that BCG can also attenuate the severity of autoimmunity. Given the unclear immunomodulatory effects of these compounds on DCs we investigated the effects of BCG and β-Glc on human monocyte-derived DCs (moDCs). Our results demonstrate that early exposure to BCG and β-Glc during moDC development steers their function towards tolerance, indicated by reduced pro-inflammatory cytokine production upon rechallenge. Additionally, BCG and β-Glc challenge hampered the moDCs' ability to mount proinflammatory IFN-γ-driven T cell responses, while mediating the enrichment of regulatory T cells. Metabolically, we potentially observe signs that BCG amplifies glycolysis but not oxidative phosphorylation. Together, our findings provide novel insights into the role of BCG and β-Glc on human DCs and support the therapeutic potential of modulating human DCs with these training agents for the treatment of autoimmune disorders.
    Keywords:  BCG; Dendritic cells; Tolerance; Trained immunity; Β-Glucan
    DOI:  https://doi.org/10.1016/j.cellimm.2025.105060
  2. Cardiovasc Res. 2026 Jan 05. pii: cvaf278. [Epub ahead of print]
    Trained immunity links cardiovascular disease and COVID-19.
    Jéssica C Dos Santos, Mihai G Netea, Niels P Riksen.
      
    DOI:  https://doi.org/10.1093/cvr/cvaf278
  3. Front Immunol. 2025 ;16 1664444
    Immunomodulation by bacterial products promotes innate signatures favorable to macrophage responses in tuberculosis infection.
    Dámaris P Romero-Rodríguez, Eduardo Montes, Héctor Isaac Rocha-González, Martha Torres, Joaquín Zúñiga, Esmeralda Juárez.
       Background: Tuberculosis remains a leading cause of death from infectious diseases globally, underscoring the need to boost innate responses in monocytes and macrophages to enhance early control of Mycobacterium tuberculosis infection. Trained immunity, a form of innate immune memory, enhances macrophage responsiveness through epigenet ic and metabolic reprogramming, offering a promising approach to strengthen host defenses against M. tuberculosis.
    Methods: This study evaluated the immunomodulatory potential of pharmaceutical-grade bacterial suspension (BS) and bacterial lysates (BL) in human monocyte-derived macrophages (MDM) and their role in innate response to M. tuberculosis infection. MDMs were stimulated with M. bovis BCG, BS, and BL following a training protocol described for BCG-dependent trained immunity.
    Results: We observed that BS and BL induced sustained cytokine responses and a metabolic transcriptional profile upon secondary stimulation with M. tuberculosis. BS and BL promoted increased IL-1b production in M. tuberculosis-infected MDMs. Additionally, the expression of surface markers shifted to high levels of CD80, CD86, HLA-DR, TLR2, and CD16 and low expression of CD163, TLR9, CCR2, and TLR4, consistent with an M1 phenotype. Moreover, BS and BL upregulated antimicrobial transcriptional signatures, including autophagy-related MAP1LC3 and ATG16L1.
    Discussion: These findings indicate that BS and BL engage training-associated transcriptional and phenotypic changes, providing new adjunctive strategies to boost innate responses in tuberculosis and other chronic infections.
    Keywords:  bacterial lysates; bacterial suspension; macrophages; metabolic immunomodulation; trained immunity; tuberculosis
    DOI:  https://doi.org/10.3389/fimmu.2025.1664444
  4. J Leukoc Biol. 2026 Jan 10. pii: qiag005. [Epub ahead of print]
    Biodegradable microparticles promote anti-inflammatory innate immune memory though a size- and mTOR dependent process.
    Roisin I Lynch, Aoife L Gorman, Sean McCluskey, Cian J H Horneck-Johnston, Kate Roche, Frederick J Sheedy, Natalia Muñoz-Wolf, Ed C Lavelle.
      Emerging evidence demonstrates that innate immune cells can maintain a non-specific memory, not only in response to microbe-associated ligands such as β-glucan, but also synthetic biomaterials and nano- and microparticles. This creates an opportunity to leverage biomaterials which can establish favourable innate immune responses and memory for therapeutic applications. In this study, we identify particle size as a critical physical determinant influencing both acute macrophage activation and long-term innate immune memory. Specifically, biodegradable poly(lactic-co-glycolic acid) particles in the 1-2 µm size range promoted an anti-inflammatory phenotype and enhanced oxidative phosphorylation in bone marrow-derived macrophages, through a process dependent on mTOR signalling. In contrast to the well documented pro-inflammatory innate immune training seen with microbial stimuli such as β-glucans, exposure of macrophages to 1-2um poly(lactic-co-glycolic acid) particles promoted a durable anti-inflammatory reprogramming, marked by elevated IL-10 and IL-1 receptor antagonist secretion upon secondary stimulation, and metabolic re-wiring. Moreover, bone marrow from mice injected with PLGA particles in this size range, were reprogrammed to upregulate IL-1Ra and IL-10 secretion upon a re-stimulation, which persisted up to one week post-injection. These findings uncover how the physicochemical properties of polymeric nanoparticles differentially modulate innate immune cells and regulate the induction of innate training.
    Keywords:  PLGA particles; anti-inflammatory; innate-training; mTOR; macrophage
    DOI:  https://doi.org/10.1093/jleuko/qiag005
  5. Immunol Rev. 2026 Jan;337(1): e70095
    Trained Immunity and Cardiovascular Risk: An Immunological Perspective.
    Katherine A Boden, Jason Chai, Tafadzwa T J Kufazvinei, Robin P Choudhury.
      Systemic inflammation is a key driver of atherogenesis and its complications. While anti-inflammatory therapies targeting pathways such as IL-1β and IL-6 have shown promise in established atherosclerotic cardiovascular disease (ASCVD), potential systemic effects raise concerns about immune suppression and infection, underscoring the need for more precise immunomodulatory approaches. Trained immunity-a form of innate immune memory-has emerged as a potential contributor linking ASCVD risk factors to chronic inflammation and disease progression. In this review, we discuss the evidence for trained immunity in ASCVD, its induction by several known risk factors (e.g., hyperglycaemia, hypercholesterolemia, diet, chronic stress, inflammatory diseases, and infection), and its potential role in sustaining vascular inflammation. Advancing our understanding of the metabolic and epigenetic mechanisms underlying trained immunity, as well as defining shared and cumulative effects across risk factors, will be critical to guide the development of next-generation targeted therapies for ASCVD prevention and treatment.
    Keywords:  cardiovascular disease; inflammation; trained immunity
    DOI:  https://doi.org/10.1111/imr.70095
  6. Cell Death Differ. 2026 Jan 08.
    ERK/Smurf1 regulates non-canonical pyroptosis by prompting Caspase-11 ubiquitination.
    Chenglong Zhu, Wangzheqi Zhang, Yan Liao, Ruoyu Jiang, Lindong Cheng, Yi Wang, Tian Zhou, Yijie Tao, Sheng Xu, Yizhi Yu, Zui Zou.
      Sepsis, a devastating microbe-induced inflammatory response, culminates in multi-organ dysfunction, with pyroptosis mediated by the non-canonical inflammasome being a pivotal factor. The mouse Caspase-11, central to this pathway, is directly activated by cytoplasmic lipopolysaccharide (LPS). Although ubiquitination is known to tightly regulate the inflammatory response in pyroptosis, its role in modulating the non-canonical inflammasome remains enigmatic. In this study, we unveil that the E3 ubiquitin ligase Smurf1 is a critical negative regulator of the non-canonical inflammasome pathway. Smurf1 orchestrates K48-linked polyubiquitination of Caspase-11 at K245 and K247 residues, leading to its degradation via the 26S proteasome. This process is further amplified by ERK phosphorylation of Smurf1 at the S148 site. In parallel, Caspase-11 modulates Smurf1 protein content through cleavage. Notably, macrophage-specific Smurf1 deficiency exacerbates sepsis-induced mortality in mice, attributed to the hyperactivation of the non-canonical inflammasome. Conversely, targeted supplementation of Smurf1 in macrophages mitigates the high mortality and inflammatory response associated with sepsis. Thus, Smurf1 emerges as a key player in modulating the activation of the non-canonical inflammasome in response to Gram-negative bacterial infections.
    DOI:  https://doi.org/10.1038/s41418-025-01654-w
  7. bioRxiv. 2025 Dec 31. pii: 2025.12.30.697125. [Epub ahead of print]
    Molecular Mechanisms of Priming Innate Immunity by Small Extracellular Vesicles Released during Infection with Gram-negative Bacteria.
    Adam Fleming, Heather Hobbs, Graham Matulis, Weidong Zhou, Valerie Calvert, Hunter Mason, Samson Omole, Shivam A Gaikwad, Cameron C Ellis, Emanuel F Petricoin, Igor C Almeida, Ramin M Hakami.
      Much still remains to understand about the underlying molecular mechanisms by which the trafficking of small extracellular vesicles (sEVs) modulates innate immune responses during infection with pathogenic Gram-negative bacteria. To address this significant gap in knowledge, we used two infection models to investigate innate immune regulation by the sEVs released from cells infected with either Yersinia pestis (Yp) or Burkholderia thailandensis (Bt), designated as EXi-Yp and EXi-Bt respectively. The EXi induced differentiation of naïve human monocytes to macrophages and triggered robust pro- inflammatory cytokine release, including release of IL-6, mirroring direct bacterial infection effects. Comprehensive cell signaling analyses revealed that the EXi modulate a small set of host signaling proteins, with p38 activation being primarily responsible for the observed protective effects. EXi-induced p38 activation leads to increased IL-6 release, which in turn is responsible for decreased bacterial survival within recipient immune cells that are subsequently infected. Consistent with the in vitro results, mice administered with EXi-Yp exhibited elevated serum IL-6 levels and were protected from Yp infection. Furthermore, using our microfluidic chip platform that allows functional interrogation of EV effects under physiologically relevant conditions, we have demonstrated that EXi exchange between Yp-infected cells and naive recipient monocytes leads to differentiation of the recipient cells to macrophages. Together, our findings reveal a largely unexplored aspect of innate immunity and provide a mechanistic model in which EXi prime local and distant naïve monocytes via p38-induced differentiation and IL-6 production to protect against infection with Gram-negative bacteria.
    DOI:  https://doi.org/10.64898/2025.12.30.697125
  8. Mucosal Immunol. 2026 Jan 07. pii: S1933-0219(26)00002-4. [Epub ahead of print]
    Trained ILC2 prevent IL-17-associated lung injury during helminth infection through a serotonin-dependent mechanism.
    Ulrich Membe Femoe, Fungai Musaigwa, Imani Nicolis, Li-Yin Hung, Camila Napuri, Chinwekele Uzoije, Heather L Rossi, Cailu Lin, Heidi Winters, Danielle R Reed, Juan Manuel Inclan-Rico, De'Broski R Herbert.
      Type 2 cytokinerelease promotes wound healing and helminth clearance, but it remains unclearwhethergroup 2 innate lymphocytes (ILC2s) and T-helper2 cells (TH2) cells have functionally distinctroles during anamnestic immunity. This study demonstrates that ILC2 can prevent re-infection andlimit tissue injury caused by the helminthNippostrongylus brasiliensis (Nb). TH2 cells were necessary during initial antigen encounter but dispensable forearly pathogen clearance and lungrepairafterILC2 priming. Upon re-infection, trained ILC2 selectively blocked interleukin (IL)-17+ γδT cell expansion and infection-induced lung injury through an Amphiregulin (Areg)-independent mechanism. Trained ILC2s had a distinct metabolic gene expression profile marked by elevated tryptophan hydroxylase 1(Tph1) and pulmonary serotonin levels were largely ILC2-dependent. Surprisingly, serotonin prevented IL-17-associated lung hemorrhage irrespective of parasite load. We propose that TH2-ILC2 interactions drive pathogen control, but ILC2 distinctly control lung tissuerepairthrough serotonin.
    Keywords:  Helminth; Lung; Serotonin; Tissue repair; Type 2 immunity; trained ILC2
    DOI:  https://doi.org/10.1016/j.mucimm.2026.01.002
  9. Cell Rep. 2026 Jan 03. pii: S2211-1247(25)01455-X. [Epub ahead of print]45(1): 116683
    Macrophage glycine transporter supports IL-1β production by modulating the AKT1/mTOR/NLRP3 pathway.
    Yan Guo, Xiaoyan Wu, Xinmei Zhang, Qilin Hu, Zhending Gan, Shijie Liu, Xuehua Mei, Xiu Zeng, Wenkai Ren.
      Increasing investigations indicate that neurotransmitters shape immune cell function; however, current results about glycine (Gly) in inflammatory macrophage responses are conflicting. Here, we found that Gly transporters support interleukin-1β (IL-1β) production in inflammatory macrophages, while Gly receptors inhibit it. Inflammatory macrophages have higher expression of Gly transporter 1 (GlyT1; also known as SLC6A9). Notably, SLC6A9 inhibition leads to extracellular accumulation of Gly and limits IL-1β production in inflammatory macrophages. Mechanically, extracellular Gly suppresses phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT1)/mammalian target of rapamycin (mTOR) signaling through the Gly receptor alpha-4 (Glrα4), thereby inhibiting activation of the NOD-like receptor 3 (NLRP3) inflammasome and IL-1β production. Furthermore, Gly supplementation or myeloid-specific SLC6A9 depletion alleviates the lipopolysaccharide (LPS)-induced inflammatory response in vivo. Collectively, our findings reveal a previously uncharacterized mechanism for the Gly-ergic system in regulating inflammatory macrophage function, providing a potential alleviating target for macrophage-associated diseases.
    Keywords:  CP: immunology; CP: metabolism; IL-1β; PI3K; SLC6A9; glycine; mTOR; macrophages
    DOI:  https://doi.org/10.1016/j.celrep.2025.116683
  10. Am J Physiol Regul Integr Comp Physiol. 2026 Jan 07.
    Neonatal lipopolysaccharide administration causes long-term changes in mouse immunosteroids.
    Melody Salehzadeh, Anna Mazurenko, Kiran K Soma.
      Early-life infections have enduring effects on the immune and endocrine systems. Glucocorticoids (GCs) are produced by the adrenal glands and also produced by lymphoid organs (immunosteroids). We investigated the impacts of early-life lipopolysaccharide (LPS) challenge on GC and mineralocorticoid regulation in blood and lymphoid organs. We administered saline vehicle (nVEH) or LPS (50 μg/kg bw, ip) (nLPS) to neonatal mice on post-natal day (PND) 4 and 6 ("first hit"). We then administered saline vehicle (aVEH) or LPS (50 μg/kg bw, ip) (aLPS) to adults on PND90 ("second hit"), in a 2×2 design. We collected whole blood, bone marrow, thymus, and spleen 4 hr after treatment at PND90. We measured 9 steroids via liquid chromatography-tandem mass spectrometry and measured transcripts of steroidogenic enzymes (Cyp11b1, Cyp11b2, Hsd11b1, Hsd11b2), GC receptor, mineralocorticoid receptor, and HPA axis components (Crh, Crhr1, Pomc, Mc2r) via RT-qPCR. The nLPS treatment did not have significant effects on blood GC levels in adulthood. Nonetheless, nLPS treatment increased corticosterone and 11-dehydrocorticosterone levels in lymphoid organs of aLPS subjects. The nLPS treatment increased aldosterone levels in blood and bone marrow of aVEH females but decreased aldosterone levels in bone marrow and thymus of aVEH males. The nLPS treatment also increased transcripts for steroidogenic enzymes, especially the aldosterone-synthetic enzyme Cyp11b2, and modulated transcripts for steroid receptors, especially MR, in lymphoid organs of aVEH and aLPS subjects. These findings suggest that elevated local GC and aldosterone production in lymphoid organs is a mechanism for the enduring effects of early-life infections on immune function.
    Keywords:  cortisol; development; early-life adversity; sepsis; stress
    DOI:  https://doi.org/10.1152/ajpregu.00135.2025
  11. Arch Biochem Biophys. 2026 Jan;pii: S0003-9861(25)00363-7. [Epub ahead of print]775 110649
    Thermotolerance induced by non-lethal heat shock at 40 °C is activated by mitochondrial ROS and is Nrf2-dependent.
    Georges Hraoui, Mélanie Grondin, Khadija Rezki, Diana A Averill-Bates.
      Hyperthermia is generally administered as an adjuvant to chemotherapy/radiotherapy and sensitizes tumors to these anticancer treatments. Repeated heat treatments (≥42 °C) cause development of transient thermotolerance, an adaptive survival response. This response can be mediated by upregulation of cellular defense pathways and remains unclear. We aim to clarify the mechanistic explanations behind activation of this response. In vitro, thermotolerance can be induced by mild heat stress at 40 °C and protects cells against subsequent lethal heat shock (≥42 °C). When HeLa cells were heated at 42 °C, cellular and mitochondrial superoxide and peroxide levels increased. Treatment with mitochondrial antioxidant MitoQ, or NADPH oxidase (NOX) inhibitor apocynin, decreased levels of reactive oxygen species (ROS) and apoptotic cell death, indicating that mitochondria and NOX are important sources of ROS at 42 °C. Mild heat stress at 40 °C increased production of ROS, which are thought to activate the adaptive response, and reduce subsequent cell death at 42 °C. Our results show that heat-derived ROS are linked to expression of master antioxidant regulator Nrf2. When Nrf2 was overexpressed or knocked down, Nrf2 expression was directly associated with protective ability of the adaptive response induced by mild heat stress (40 °C). Mitochondrial ROS were found to be essential in mediating Nrf2-dependent thermotolerance, because MitoQ treatment prior to exposure to 40 °C reduced Nrf2 levels and dissipated the subsequent protective effect of thermotolerance against toxicity at 42 °C. Our study demonstrates that specific sources of ROS had biologically different implications in activating Nrf2, underlining potential therapeutic targets that may contribute to thermotolerance in anticancer treatments.
    Keywords:  Adaptive survival response; Heat shock; Mitochondria; Nrf2; Oxidative stress; Thermotolerance
    DOI:  https://doi.org/10.1016/j.abb.2025.110649
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