bims-traimu Biomed News
on Trained immunity
Issue of 2025–05–18
thirteen papers selected by
Yantong Wan, Southern Medical University
  1. Salmonella LVR01 triggers antagonistic two-armed innate immune memory that impacts on antitumor efficacy.
  2. Trained immunity-based Adjuvated vaccines (TIbAV) approach: β-glucans as example.
  3. Candida albicans-stimulated hematopoietic stem and progenitor cells generate trained neutrophils with enhanced mitochondrial ROS production that defend against infection.
  4. Superior protective efficacy of genotype IVa-based single-cycle viral hemorrhagic septicemia virus (VHSV) vaccine compared to formalin-killed VHSV vaccine against VHSV genotype Ia in rainbow trout (Oncorhynchus mykiss).
  5. Efficacy of BCG vaccination against COVID-19 in health care workers and non-health care workers: A meta-analysis of randomized controlled trials.
  6. Investigating endogenous immune-mediated monocyte memory in rheumatoid arthritis.
  7. Impaired LPS Tolerance in Monocytes of Coronary Atherosclerosis Patients Is Associated with the Intermediate Subset.
  8. Bone marrow mesenchymal stem cell-derived exosomes alleviating sepsis-induced lung injury by inhibiting ferroptosis of macrophages.
  9. Fever-range temperature alters continual efferocytosis mediated by mouse pro-inflammatory macrophages.
  10. CD300ld Promotes Neutrophil Bacterial Phagocytosis in Sepsis.
  11. NRF1 coordinates mitochondrial adaptations to dampen intracellular ROS and inflammatory responses during ischemia reperfusion.
  12. Platelet NLRP6 protects from microvascular thrombosis in sepsis.
  13. IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity.
  1. Front Immunol. 2025 ;16 1535131
    Salmonella LVR01 triggers antagonistic two-armed innate immune memory that impacts on antitumor efficacy.
    Sofía Chilibroste, Jéssica C Dos Santos, Amy Mónaco, Leo A B Joosten, María Moreno, José A Chabalgoity.
      The current understanding of innate immune memory encompasses both trained immunity and immune tolerance, where cells can exhibit enhanced responsiveness or immune paralysis upon subsequent stimuli, respectively. Various agents induce either of these responses, including β-glucan, Leishmania, BCG and LPS. BCG is a clinically approved immunotherapy for bladder cancer and BCG-induced trained immunity is important in driving anti-tumor adaptive immunity. Salmonella also shows promise in cancer treatment, eliciting potent anti-tumor immune responses, but with transitory effects. This led us to investigate whether Salmonella LVR01, like BCG, triggers trained immunity and its impact on anti-tumor responses. Herein, we report that Salmonella induces an enhanced response in bone marrow cells, characterized by a robust cytokine response upon a second stimulus, in a fashion that resembles trained immunity. Coherently with that, Salmonella administration induces enhanced responsiveness to a tumor implanted later in time, resulting in slow tumor growth and extended survival. However, in vitro stimulation of human monocytes and murine bone-marrow derived myeloid-enriched cells with Salmonella results in decreased production of cytokines resembling immune paralysis. Overall, our results suggest that Salmonella LVR01 induces enhanced responses of innate immune memory, as well as paralysis on monocytes. These two antagonistic effects could be the basis of the transitory effect of Salmonella treatment and suggest that further investigation on these phenomena could shed light on how to improve Salmonella-based immunotherapies for cancer.
    Keywords:  Salmonella; anti-tumor Immunity; cancer immunotherapies; innate immune memory; tolerance; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2025.1535131
  2. Vaccine. 2025 May 10. pii: S0264-410X(25)00537-7. [Epub ahead of print]57 127240
    Trained immunity-based Adjuvated vaccines (TIbAV) approach: β-glucans as example.
    Miriam Angulo, Abel Ramos-Vega, Carlos Angulo.
      The induction of trained immunity (TRIM) has emerged as an approach to fight against diseases. Several β-glucans and vaccines have been identified as trained immunity inductors, allowing heterologous protection for infectious diseases. Curiously, β-glucans from yeast, fungal, and plant species have been evaluated in clinical trials as vaccine adjuvants to combat infectious and non-communicable diseases. However, their adjuvant use for trained immunity-based vaccines (TIbV) remains scarcely studied. In this context, this review brings a scientific panorama of β-glucans and vaccines and offers perspectives on their combination to potentiate trained immunity induction and its benefits. In agreement with TRIM and TIbV concepts, we propose trained immunity-based adjuvanted vaccines (TIbAV) to refer to studies regarding this approach.
    Keywords:  Antigen; Carbohydrate; Health; Innate immune memory; Vaccination
    DOI:  https://doi.org/10.1016/j.vaccine.2025.127240
  3. PLoS Pathog. 2025 May 13. 21(5): e1013170
    Candida albicans-stimulated hematopoietic stem and progenitor cells generate trained neutrophils with enhanced mitochondrial ROS production that defend against infection.
    María Sobén, Paula Guerrero, Andrea Guiu, Alberto Yáñez, M Luisa Gil.
      Central trained immunity, induced via reprogramming of hematopoietic stem and progenitor cells (HSPCs), mediates sustained heightened responsiveness of mature myeloid cells to secondary challenges. We have previously demonstrated that HSPCs use TLR2 and Dectin-1 to sense Candida albicans to induce the production of trained monocytes/macrophages to fight against secondary infection. Neutrophils play an important role in innate immunity and are critical for clearance of C. albicans. In this work, we used an in vitro model of mouse HSPC differentiation to investigate the functional phenotype of neutrophils derived from HSPCs exposed to various PAMPs and C. albicans cells. We found that neutrophils derived from HSPCs stimulated by a TLR2 agonist exhibit reduced inflammatory cytokine production (tolerized neutrophils) whereas neutrophils generated from a Dectin-1 agonist or C. albicans stimulated HSPCs produce higher amounts of cytokines (trained neutrophils). We further demonstrated that a transient exposure of HSPCs to live C. albicans cells is sufficient to induce a trained phenotype of the neutrophils they produce in a Dectin-1- and TLR2-dependent manner. These trained neutrophils exhibited higher phagocytosis and microbicidal capacity than control neutrophils. Additionally, their adoptive transfer was sufficient to reduce fungal burden during invasive candidiasis. Mechanistically, we demonstrated that trained neutrophils use mitochondrial ROS (mtROS) to enhance their ability to kill C. albicans cells, as they produce higher amounts of mtROS and scavenging mtROS with MitoTEMPO attenuated their yeast-killing ability to match that of control neutrophils. Altogether, these data suggest that infection-experienced HSPCs contribute to trained immunity by providing a source of trained neutrophils with enhanced antimicrobial activity which may confer prolonged protection from infection. The tailored manipulation of this mechanism might offer new therapeutic strategies for controlling fungal infections by harnessing neutrophils.
    DOI:  https://doi.org/10.1371/journal.ppat.1013170
  4. Fish Shellfish Immunol. 2025 May 11. pii: S1050-4648(25)00298-0. [Epub ahead of print]163 110409
    Superior protective efficacy of genotype IVa-based single-cycle viral hemorrhagic septicemia virus (VHSV) vaccine compared to formalin-killed VHSV vaccine against VHSV genotype Ia in rainbow trout (Oncorhynchus mykiss).
    Kyung Min Lee, So Yeon Kim, Ki Hong Kim.
      Current viral vaccine strategies for aquaculture primarily target homologous viral infections through adaptive immune responses. However, the emergence of diverse genetic variants of viral hemorrhagic septicemia virus (VHSV) poses a significant challenge to aquaculture, necessitating vaccines capable of providing broad-spectrum cross-protection. This study aimed to compare the protective efficacy of a formalin-killed virus (FKC) vaccine and a single-cycle VHSV (rVHSV-ΔG) vaccine, both based on VHSV genotype IVa, against a heterologous VHSV genotype Ia challenge in rainbow trout (Oncorhynchus mykiss). Upon heterologous challenge with VHSV genotype Ia, the rVHSV-ΔG vaccine demonstrated superior protective efficacy relative to the FKC vaccine. Despite comparable levels of cross-reactive antibody titers and Type I interferon responses among the experimental groups, the rVHSV-ΔG group exhibited significantly elevated expression of pro-inflammatory cytokines (tnf-α, il-1β, and il-6) and the chemokine cxcl8 following challenge, suggesting an important role of innate immune mechanisms in mediating the enhanced protective effect. Notably, elevated levels of histone modifications (H3K4me3, H3K27ac) at the promoter regions of these cytokine genes suggest that rVHSV-ΔG may induce trained immunity. These results indicate that live VHSV vaccines may leverage innate immune memory to promote strong pro-inflammatory responses, representing a promising strategy for cross-protection against diverse VHSV variants.
    Keywords:  Cross-genotype protection; Formalin-killed VHSV; Histone modification; Pro-inflammatory cytokines; Rainbow trout; Single-cycle VHSV; rVHSV-ΔG
    DOI:  https://doi.org/10.1016/j.fsi.2025.110409
  5. PLoS One. 2025 ;20(5): e0321511
    Efficacy of BCG vaccination against COVID-19 in health care workers and non-health care workers: A meta-analysis of randomized controlled trials.
    Zhuoyang Xia, Jiahao Meng, Xuanyu Wang, Pan Liu, Yumei Wu, Yilin Xiong, Baimei He, Shuguang Gao.
       BACKGROUND: The Bacillus Calmette-Guérin (BCG) vaccine has shown potential non-specific protection against infectious diseases through "trained immunity", which may offer cross-protection against viral infections. However, there is no consensus on whether BCG vaccination could prevent COVID-19 or reduce its symptoms.
    METHODS: PubMed, Cochrane Library, Embase and Web of Science were searched for randomized controlled trials on BCG vaccination and COVID-19 prevention, covering studies from the inception of each database to 2 May 2024. We included studies where participants, not infected with COVID-19, were vaccinated with BCG or placebo. We excluded non-randomized trials, studies without full texts, unrelated interventions, and those not reporting relevant outcomes. Clinical data on COVID-19 infection, severity, hospitalization, mortality, and other adverse events, were extracted and analyzed. The DerSimonian-Laird random-effects model and the Cochrane Collaboration's risk of Bias Tool were used for analysis and risk of bias assessment.
    RESULTS: A total of 12 RCTs involving 18,086 patients were finally included. For the prophylactic effect of BCG on COVID-19, pooled results showed no statistically significant difference between BCG and placebo (pooled RR 1.02; 95%CI: 0.91-1.14). There was no statistically significant difference between non-health care workers (pooled RR 0.91; 95%CI: 0.67-1.24) and health care workers (pooled RR 1.03; 95%CI: 0.93-1.15). Regarding COVID-19 severity, no significant difference were found for asymptomatic (pooled RR 1.18; 95%CI: 0.81-1.72), mild to moderate (pooled RR 0.99; 95%CI: 0.84-1.17), severe COVID-19 (pooled RR 1.25; 95%CI: 0.92-1.70), hospitalization (pooled RR 0.93; 95%CI: 0.58-1.50) or all-cause mortality (pooled RR 0.60; 95%CI: 0.18-1.95) between BCG and placebo groups. Subgroup analysis also showed no significant difference between BCG and placebo in non-health care workers or health care workers.
    CONCLUSIONS: Vaccination of BCG could not effectively prevent COVID-19 infection or decrease COVID-19 symptoms both in non-health care workers and health care workers.
    DOI:  https://doi.org/10.1371/journal.pone.0321511
  6. Ann Rheum Dis. 2025 May 10. pii: S0003-4967(25)00883-0. [Epub ahead of print]
    Investigating endogenous immune-mediated monocyte memory in rheumatoid arthritis.
    Anna M Marzeda, Anja Schwenzer, Bogdan S Didov, Kieran Woolcock, Jean-Baptiste Richard, Libby K Jennings, Amélie M Julé, Nan Yang, Sarah Davidson, Steve Sansom, Adam P Cribbs, Calliope A Dendrou, Wyatt W Yue, Carl S Goodyear, Karim Raza, Kim S Midwood.
       OBJECTIVES: Inflammation triggered by endogenous stimuli that signal cellular stress or tissue injury must be tightly controlled to balance robust protection from intrinsic danger while avoiding catastrophic destruction of healthy tissues. Here, we assess the contribution of innate memory to this balance.
    METHODS: Memory evoked by the extracellular matrix protein tenascin-C, a damage-associated, toll-like receptor 4 (TLR4) agonist, was compared to that induced by the pathogenic TLR4 agonist lipopolysaccharide (LPS) by transcriptomic and epigenetic profiling of monocytes from healthy individuals or people wirh rheumatoid arthritis (RA), and tissue macrophages from the RA synovium.
    RESULTS: Tenascin-C reprograms monocyte response to subsequent threats, inducing concomitantly suppressed and enhanced responses to rechallenge. Comparative analysis of tenascin-C and LPS revealed common and distinct gene expression signatures, effects controlled transcriptionally and associated with stimulus-specific epigenetic mediators. Altered responses following rechallenge after priming with tenascin-C were not limited to subsequent TLR4 activation but were evident in response to various pathogenic and endogenous stimuli detected by different receptors. In healthy monocytes primed with tenascin-C, rechallenge with stimuli found at high levels in the joints of people with RA resulted in trained responses that were not induced by LPS, including genes associated with chronic inflammation, tissue destruction, altered metabolism, and poor treatment response in RA. The expression of a large subset of these genes was elevated in monocytes from people with RA in the absence of any stimulation and in RA synovial macrophage populations associated with disease flare. Moreover, higher levels of permissive complexes within key epigenetic nodes and increased bivalent modification creating poised loci within endogenously trained genes were observed in RA cells.
    CONCLUSIONS: These data highlight how innate reprogramming during 'sterile' inflammatory diseases contributes to chronicity, uncovering pathways unique to endogenous immune triggers that could provide disease-specific points of intervention without engendering global immune suppression.
    DOI:  https://doi.org/10.1016/j.ard.2025.03.016
  7. J Leukoc Biol. 2025 May 12. pii: qiaf060. [Epub ahead of print]
    Impaired LPS Tolerance in Monocytes of Coronary Atherosclerosis Patients Is Associated with the Intermediate Subset.
    Nikita G Nikiforov, Yegor S Chegodaev, Svetlana S Verkhova, Elena A Pudova, Mikhail A Popov, Anna V Tvorogova, Alexander D Zhuravlev, Ruslan A Maslennikov, Anastasiya V Snezhkina, Anna V Kudryavtseva, Yegor E Yegorov, Andrey V Omelchenko, Daria D Borodko, Dmitry I Zybin, Dmitry V Shumakov, Alexander N Orekhov.
      Endotoxin tolerance in monocytes is a mechanism that reduces the secretion of inflammatory cytokines upon repeated pathogen exposure, thereby protecting tissues from hyperinflammation. Previously, we demonstrated that monocytes from patients with asymptomatic carotid atherosclerosis exhibit impaired LPS tolerance. In this study, we aimed to investigate monocyte tolerance impairments in coronary atherosclerosis in greater detail. The study included 46 male patients with ischemic heart disease, divided into two groups based on coronary angiography results: with and without coronary atherosclerosis. CD14+ monocytes were isolated from patients' blood and subjected to LPS stimulation on days 1 and 7 of culture. Transcriptomic analysis of monocytes was conducted. Monocyte subpopulations were assessed and sorted based on CD14 and CD16 expression. Patients with coronary atherosclerosis exhibited disrupted inflammatory responses in monocytes, characterized by elevated basal and LPS-induced IL-1β secretion. These patients demonstrated impaired LPS tolerance, as evidenced by increased CCL2 secretion upon repeated stimulation. Transcriptomic analysis revealed upregulation of inflammatory genes, particularly those associated with minor CD16+ monocyte subpopulations. The proportions of non-classical and intermediate monocytes were elevated in patients with atherosclerosis, with IL-1β and CCL2 secretion levels correlating predominantly with the intermediate monocyte subset. Functional analysis revealed that non-classical monocytes from healthy donors developed stable endotoxin tolerance. In contrast, intermediate and classical monocytes from some donors exhibited a non-tolerant response to LPS, as evidenced by secretion of IL-1β, IL-6 and CCL2. The differentiation of classical monocytes into intermediate monocytes may play a key role in the impaired endotoxin tolerance observed in atherosclerosis.
    Keywords:  CCL2; CD16; IL-1β; LPS tolerance; coronary atherosclerosis; inflammation; intermediate monocytes
    DOI:  https://doi.org/10.1093/jleuko/qiaf060
  8. Int Immunopharmacol. 2025 May 13. pii: S1567-5769(25)00779-9. [Epub ahead of print]158 114789
    Bone marrow mesenchymal stem cell-derived exosomes alleviating sepsis-induced lung injury by inhibiting ferroptosis of macrophages.
    Huimin Deng, Wenyu Zhou, Juan Wei, Tian Jin, Yuanli Chen, Lina Zhu, Hao Yang, Xin Lv.
       OBJECTIVE: To investigate whether bone marrow mesenchymal stem cells derived exosomes (BMSCs-exo) can alleviate sepsis-induced lung injury and its related mechanism by inhibiting ferroptosis of macrophages.
    METHODS: RAW264.7 cells were first stimulated with lipopolysaccharide (LPS) to observe whether macrophage ferroptosis occurred. After pre-treating BMSCs with the exosome inhibitor GW4869, the lung-protective effect was observed to determine if it was eliminated. Furthermore, BMSCs-exo was extracted to clarify if it could exert effects like BMSCs. Finally, key molecules responsible for the effects were identified through sequencing and other related techniques.
    RESULTS: Following stimulation with LPS, the expression of GPX4 in RAW264.7 cells decreased significantly, while the expression of PTGS2 increased significantly. The intracellular GSH content decreased, while MDA content increased. BMSCs-exo reversed the decrease in GPX4 and increase in PTGS2, increased GSH and decreased MDA. Sequencing revealed that lncRNA SNHG12 in macrophages was significantly upregulated after co-culture with BMSCs-exo. Knockdown of lncRNA SNHG12 in BMSCs via siRNA resulted in a significant decrease in the inhibitory effect on macrophage ferroptosis both in vivo and in vitro.
    CONCLUSION: BMSCs-exo can inhibit macrophage ferroptosis through lncRNA SNHG12, thereby alleviating the sepsis-induced lung injury and improving the survival rate.
    Keywords:  Acute respiratory distress syndrome; Bone marrow mesenchymal stem cells; Exosome; Ferroptosis; Macrophages
    DOI:  https://doi.org/10.1016/j.intimp.2025.114789
  9. J Leukoc Biol. 2025 May 14. pii: qiaf061. [Epub ahead of print]
    Fever-range temperature alters continual efferocytosis mediated by mouse pro-inflammatory macrophages.
    Mathieu Vetter, Melissa Maraux, Francis Bonnefoy, Ludivine Dal Zuffo, Baptiste Lamarthée, Gwenaël Rolin, Audrey Wetzel, Sylvain Perruche, Paul Peixoto, Philippe Saas.
      Fever, a cardinal sign of inflammation, has been shown to modulate macrophage functions. Here, we investigate whether fever affects macrophage efferocytosis. This process is essential for the resolution of inflammation and the return to homeostasis with the reprogramming of macrophages towards a pro-resolving phenotype. Using primary mouse bone marrow-derived macrophages stimulated with lipopolysaccharide and interferon-γ (i.e., pro-inflammatory macrophages), we first validated that exposure to febrile temperature (39.5°C) induced a heat shock protein response. Then, we observed that febrile temperature decreased the capacity of pro-inflammatory macrophages to uptake apoptotic cells. This reduced efferocytic capacity of macrophages exposed to febrile temperature resulted from a decreased capacity to interact with apoptotic cells and to internalize these dying cells. Exposure to febrile temperature reduced the cell motility of macrophages in response to apoptotic cells, as assessed by IncuCyte® live-cell imaging. RNA sequencing analysis of pro-inflammatory macrophages exposed to febrile temperature identified an upregulation of the Adam17 gene. As this gene encodes a protease that sheds the efferocytic receptor Mer, we determined cell surface expression of Mer and quantified soluble Mer in the culture supernatants of pro-inflammatory macrophages exposed to febrile temperature. While febrile hyperthermia induced the Mer cleavage from the cell surface of pro-inflammatory macrophages, ADAM17 inhibition during exposure to febrile temperature did not restore the efferocytic capacity of pro-inflammatory macrophages. Thus, reduction of Mer expression induced by hyperthermia did not represent the main mechanism explaining reduced efferocytosis. Nevertheless, our work suggests that fever, by decreasing efferocytic capacity of macrophages, maintains their pro-inflammatory state.
    Keywords:  Efferocytosis; apoptotic cells; fever; inflammation; macrophage
    DOI:  https://doi.org/10.1093/jleuko/qiaf061
  10. J Leukoc Biol. 2025 May 16. pii: qiaf063. [Epub ahead of print]
    CD300ld Promotes Neutrophil Bacterial Phagocytosis in Sepsis.
    Yuichi Akama, Atsushi Murao, Monowar Aziz, Ping Wang.
      Sepsis is a life-threatening condition caused by a dysregulated immune response to infection. Neutrophils act as first line of defense against infection, but their function can become impaired in sepsis. CD300 antigen-like family member d (CD300ld), predominantly expressed on neutrophils, associates with Fc receptor common gamma-chain (FcRγ chain), a component vital for phagocytosis. In this study, we investigated the role of CD300ld in neutrophil phagocytosis. Our results demonstrate a marked decrease in CD300ld expression on neutrophils isolated from both septic mice and patients. CD300ld was positively correlated with bacterial phagocytosis in neutrophils. The transcriptomic analysis of CD300ld knock-out (KO) neutrophils revealed a downregulation of genes related to defense response to bacteria, suggesting that CD300ld is a key modulator of bacterial clearance. Stimulation of CD300ld with an agonist antibody in neutrophils led to the activation of Rac2, a key regulator of actin polymerization, facilitating the enhanced phagocytosis. Furthermore, CD300ld activation significantly enhanced the in vitro phagocytosis of E. coli and S. aureus by neutrophils. Septic mice adoptively transferred with CD300ld-activated neutrophils exhibited markedly reduced bacterial loads in the blood and peritoneum, decreased inflammatory cytokine levels, and alleviated organ injury. These findings highlight the critical role of CD300ld signaling in neutrophil-mediated bacterial clearance in sepsis and provide a solid foundation for future research aimed at developing novel immunotherapies against this deadly disease condition.
    Keywords:  CD300ld; Neutrophil; Phagocytosis; Rac2; Sepsis
    DOI:  https://doi.org/10.1093/jleuko/qiaf063
  11. Cell Death Discov. 2025 May 15. 11(1): 236
    NRF1 coordinates mitochondrial adaptations to dampen intracellular ROS and inflammatory responses during ischemia reperfusion.
    Jiakun Li, Jiawei Yan, Guowei Tu, Wenjiao Jiang, Yue Qiu, Ying Su, Changhong Miao, Zhe Luo, Tiffany Horng.
      Ischemia reperfusion injury (IRI) is commonly seen in surgical procedures involving cardiopulmonary bypass and post-shock reperfusion. Sudden restoration of blood flow after a period of ischemia triggers a rapid accumulation of reactive oxygen species (ROS) and oxidative stress that promote pathological injury. Macrophage-derived inflammatory responses are also thought to contribute to such injury, but how ROS influences tissue macrophages and their elaboration of inflammatory cytokines in IRI remains poorly understood. In this study, we showed that macrophages mobilize mitochondrial adaptations during reoxygenation, including mitochondrial fission and ubiquitin proteasome system (UPS) flux. Furthermore, the transcription factor Nuclear Factor Erythroid 2 Like 1 (NRF1) is rapidly induced during reoxygenation in response to rising levels of ROS. Induction of NRF1 upregulates ubiquitin proteasome system (UPS) and mitophagy pathways to mediate mitochondrial fusion/fission dynamics and dampen ROS production, allowing for alleviation of oxidative stress and the inflammatory response. Conversely, the absence of myeloid NRF1 leads to increased ROS, driving enhanced inflammation and kidney injury in a mouse model of IRI. We thus identify macrophage NRF1 as a master regulator of mitochondrial homeostasis, antioxidant defense, and inflammatory responses in IRI.
    DOI:  https://doi.org/10.1038/s41420-025-02461-5
  12. Blood. 2025 May 15. pii: blood.2025028739. [Epub ahead of print]
    Platelet NLRP6 protects from microvascular thrombosis in sepsis.
    Huimin Jiang, Shuang Chen, Xiang Gui, Yingying Li, Yueyue Sun, Hui Zhu, Yue Dai, Jie Zhang, Xiaoqian Li, Wen Ju, Zhenyu Li, Lingyu Zeng, Kailin Xu, Jianlin Qiao.
      Sepsis is characterized by a systemic inflammation and microvascular thrombosis induced by infection. NLRP6 possesses both pro- and anti-inflammatory effects with cell-type- or tissue-specific functions. However, the role of cell-type-specific NLRP6 in sepsis remains poorly understood. In the present study, we detected NLRP6 expression in platelets. By using platelet-specific NLRP6 knockout mice and the cecal ligation and puncture model of sepsis, we demonstrated that deletion of platelet NLRP6 increased the mortality, enhanced microvascular thrombosis in the lung and liver, and promoted platelet activation, platelet-neutrophil interactions as well as the neutrophil extracellular traps (NETs) formation following sepsis. Platelet function analysis in vitro showed that deletion of NLRP6 enhanced platelet aggregation, activation, and granules release. In addition, NLRP6 deletion promoted platelet NF-κB signaling via sustaining TAB1 expression independent of the inflammasome. Moreover, inhibition of NF-κB signaling abolished the aggravated effects of the absence of platelet NLRP6 on the intravascular microthrombosis and NETs formation in sepsis and increased the overall survival. Mechanistically, NLRP6 facilitated the interaction between TRIM21 and TAB1 in activated platelets, resulting in K48-linked polyubiquitination of TAB1 and subsequent degradation. Finally, sepsis plasma triggered TAB1 degradation mediated by NLRP6/TRIM21 in normal healthy platelets through TLR4/MyD88. Our study identifies a novel protective role of platelet NLRP6 in the microvascular thrombosis during sepsis, implying it as a novel target for the treatment of sepsis.
    DOI:  https://doi.org/10.1182/blood.2025028739
  13. Cell Rep. 2025 May 09. pii: S2211-1247(25)00465-6. [Epub ahead of print]44(5): 115694
    IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity.
    Michael J McFadden, Mack B Reynolds, Britton C Michmerhuizen, Einar B Ólafsson, Sofia M Marshall, Faith Anderson Davis, Tracey L Schultz, Takao Iwawaki, Jonathan Z Sexton, Mary X D O'Riordan, Teresa R O'Meara.
      The mammalian endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) is essential for cellular homeostasis and plays key roles in infection responses, including innate immunity and microbicidal activity. While IRE1α functions through the IRE1α-XBP1S axis are known, its XBP1S-independent roles are less well understood, and its functions during fungal infection are still emerging. We demonstrate that Candida albicans activates macrophage IRE1α via C-type lectin receptor signaling independent of protein misfolding, suggesting non-canonical activation. IRE1α enhances macrophage fungicidal activity by promoting phagosome maturation, which is crucial for containing C. albicans hyphae. IRE1α facilitates early phagosomal calcium flux post-phagocytosis, which is required for phagolysosomal fusion. In macrophages lacking the IRE1α endoribonuclease domain, defective calcium flux correlates with fewer ER-early endosome contact sites, suggesting a homeostatic role for IRE1α-promoting membrane contact sites. Overall, our findings illustrate non-canonical IRE1α activation during infection and a function for IRE1α in supporting organelle contact sites to safeguard against rapidly growing microbes.
    Keywords:  CP: Immunology; CP: Microbiology; Candida albicans; IRE1α; calcium; fungal infection; innate immunity; phagosome
    DOI:  https://doi.org/10.1016/j.celrep.2025.115694
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