bims-traimu 2026-09-13 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–09–13
sixteen papers selected by
Yantong Wan, Southern Medical University

The Interplay between Innate Immune Memory and Adaptive Immunity: Emerging Mechanisms in Alloimmunity.
Trained immunity induction by β-glucan under distinct immune training schemes in a mouse model.
Differential effects of BCG-Russia and BCG-TICE on trained immunity: Potential implications for bladder cancer immunotherapy.
Immunometabolism drives metabolic and infectious disease progression through bidirectional metabolic reprogramming and epigenetic remodeling.
Trained immunity in hyperuricemia and gout: Targeting epigenetic marks to reduce cardiovascular risk.
In vitro priming with Mycobacterium fortuitum induces trained immunity-associated phenotypes in caprine alveolar macrophages and enhances phagosomal maturation and antimicrobial functions upon homologous re-stimulation.
The C3-C3aR axis modulates trained immunity in alveolar macrophages.
Epigenetic profiling reveals M1 macrophages as the primary drivers of trained immunity in HSV-1 latently infected mice.
Itaconate.
Prior Toll-like receptor 3 stimulation abolishes the ability of a MAPK/ERK kinase inhibitor to increase lipopolysaccharide-induced nitric oxide production concomitant with tumor necrosis factor-α suppression.
Macrophages tune NK cell IFNγ production through direct lipid transfer.
Interleukin-39 is a Prognostic Biomarker and Therapy Target for Sepsis.
Microbial adhesion promotes Piezo1 activation to initiate innate immunity.
β-Glucan alleviates colitis by remodeling the colonic microenvironment and promoting interleukin-33-driven active eosinophil differentiation.
Previous malaria exposure attenuates monocyte-driven inflammation and correlates with modulation of the B cell response.
To Die or Not to Die: How Sublethal Damage Rewires Cell Fate and Implications for Sepsis.

Am J Transplant. 2026 Sep 07. pii: S1600-6135(26)02750-4. [Epub ahead of print]

The Interplay between Innate Immune Memory and Adaptive Immunity: Emerging Mechanisms in Alloimmunity.

Maaike Jacobs, Lisanne C de Jong, Nils Rother, Luuk B Hilbrands, Leo A B Joosten, Willem J M Mulder, Mihai G Netea, Raphaël Duivenvoorden.

  Innate immune memory is increasingly recognized as a regulator of immune responses in solid organ transplantation. Following an initial stimulus, innate immune cells and their progenitors can undergo epigenetic and metabolic reprogramming, resulting in enhanced or suppressed pro-inflammatory responses upon subsequent encounters, termed trained immunity and innate immune tolerance, respectively. These antigen-independent forms of innate immune memory are complemented by donor-specific innate immune memory. Importantly, innate immune memory may influence alloimmune responses by shaping adaptive T cell activation through altered cytokine production, antigen presentation, and co-stimulatory signals. Conversely, adaptive immune cells can regulate the induction of innate immune memory, highlighting a bidirectional innate-adaptive crosstalk. In this review, we discuss the interplay of innate immune memory with adaptive immunity, and the potential to harness this mechanism to promote graft survival and long-term tolerance.

Keywords:  Immune modulation; adaptive immunity; immunobiology; innate allorecognition; innate immune memory; nanobiology; targeted medicine; trained immunity

DOI:  https://doi.org/10.1016/j.ajt.2026.09.007
Immunol Res. 2026 Sep 10. pii: 108. [Epub ahead of print]74(1):

Trained immunity induction by β-glucan under distinct immune training schemes in a mouse model.

Miriam Angulo, Carlos Angulo.

  Although trained immunity has been explored in various experimental models, the effects of oral β-glucan administration in mice and in vivo comparisons of different training intervals remain unexplored. First, this study evaluated the ability of β-glucan from Debaryomyces hansenii CBS 8339 (βG-Dh) to induce trained immunity in mice through oral administration at different doses. BALB/c mice received oral βG-Dh (0.5, 1, or 2 mg), oral zymosan (1 mg), or intraperitoneal zymosan (1 mg; positive control), followed by ex vivo stimulation of splenocytes with LPS. Low (0.5 mg) and medium (1 mg) doses of βG-Dh significantly enhanced cell viability, nitric oxide production, and myeloperoxidase activity. βG-Dh also increased glucose consumption and lactate production, indicating glycolytic changes associated with trained immunity. In addition, different training schemes were assessed by varying the time intervals (7, 11, and 15 days) between stimulus and challenge. Only the long-time protocol was associated with higher cell survival, increased myeloperoxidase activity, and metabolic changes consistent with a trained immunity phenotype. Overall, these results highlight the critical role of both dosage and stimulation interval in shaping trained immunity outcomes and provide new insights for optimizing β-glucan-based strategies to modulate innate immune memory.

Keywords:  Functional carbohydrates; Heterologous protection; Immunological parameters; Immunometabolism; Yeast probiotic

DOI:  https://doi.org/10.1007/s12026-026-09840-9
PLoS One. 2026 ;21(9): e0357950

Differential effects of BCG-Russia and BCG-TICE on trained immunity: Potential implications for bladder cancer immunotherapy.

Richard W Nauman, Peter A Greer, Andrew W Craig, Tiziana Cotechini, D Robert Siemens, Charles H Graham.

In recent years, immunotherapy of patients with higher-risk non-muscle invasive bladder cancer (NMIBC) in North America has relied on the use of the TICE strain of BCG. However, limitations in the supply chain have warranted investigation of the therapeutic benefit of other strains of BCG, such as BCG-Russia. Trained immunity, a form of innate immune memory, is now widely believed to be an important component of the therapeutic benefit of BCG. Therefore, in the present study we compared the effects of BCG-TICE and BCG-Russia on the acquisition of trained immunity and related secondary immune responses. C57BL/6 mice received a single intravenous injection of BCG-Russia or BCG-TICE. Four weeks later, bone marrow was collected for flow cytometric analysis of hematopoietic stem and progenitor cell (HSPC) populations, generation of bone marrow-derived macrophages, functional assessment of trained immunity, and transcriptomic profiling. Compared with BCG-Russia, BCG-TICE elicited increased levels of trained immunity, characterized by higher production of several proinflammatory cytokines upon secondary activation. BCG promoted the expansion of HSPCs independent of strain. BCG-TICE was linked to upregulation of key inflammation-related genes and enrichment of functionally relevant pathways. The results of this study reveal strain-dependent differences in the ability of BCG to induce innate immune memory and inflammatory pathways that could ultimately determine efficacy of immunotherapy of patients with NMIBC.

DOI: https://doi.org/10.1371/journal.pone.0357950
Front Immunol. 2026 ;17 1914506

Immunometabolism drives metabolic and infectious disease progression through bidirectional metabolic reprogramming and epigenetic remodeling.

Wenbin Tan.

  Immunometabolism has become a central mechanism governing innate and adaptive immune responses. The field has moved from cataloguing metabolic shifts during immune activation to understanding how specific pathways control immune cell fate and function. This review brings together current knowledge on immunometabolic regulation in metabolic and infectious diseases, emphasizing bidirectional crosstalk between these domains. We address controversies over whether inflammation causes insulin resistance or follows from it, examine the distinct metabolic programs of different immune cell types, and explore trained immunity as a link between innate immune memory and metabolic disease. The review also covers pathogen-specific metabolic strategies and host countermeasures, surveys emerging immunometabolic therapies, and flags unresolved questions for future work. Among promising strategies, mechanistic target of rapamycin (mTOR) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have advanced to clinical trials for immunometabolic indications, whereas epigenetic reprogramming and nanoparticle-based metabolic delivery remain in preclinical development.

Keywords:  epigenetic remodeling; immunometabolism; infection; inflammation; innate immune memory; metabolic diseases; metabolic reprogramming; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1914506
Curr Opin Pharmacol. 2026 Aug 13. pii: S1471-4892(26)00060-3. [Epub ahead of print]91 102664

Trained immunity in hyperuricemia and gout: Targeting epigenetic marks to reduce cardiovascular risk.

Nils Asmann, Brenda Kischkel, Leo A B Joosten.

While the link between hyperuricemia (HU) and gout with major adverse cardiovascular events (MACE) is well established, the underlying mechanism remains poorly understood. Here, we propose that this mechanism is rooted in trained innate immunity in myeloid cells as well as vascular endothelial cells. Soluble urate is a low-grade damage associated molecular pattern (DAMP) similar to already established stimuli that induce trained immunity and thereby establishes persistent epigenetic pro-inflammatory histone modifications (H3K4me1, H3K4me3, H3K27ac) increasing chromatin accessibility at particular gene regions. In addition, we suggest this is further amplified during acute gout flares through systemic IL-1β release that introduces the changes within the hematopoietic stem and progenitor cells (HSPCs). The HSPCs reprogramming leads to increased myelopoiesis which results in hyper-reactive myeloid cells. Together with the primed vasculature, we hypothesize that maladaptive epigenetic rewiring is the core mechanism that links HU and gout to MACE upon an additional secondary metabolic stressor. Hence, we introduce a three-pillar model (1. local priming, 2. Central amplification, 3. Peripheral acceleration) that captures the spatiotemporal axis of this process. While classic gout treatments manage symptoms, they leave the epigenetic landscape untouched. We therefore discuss epidrugs and cell-specific nanomedicine deliveries as compelling strategies to reverse the maladaptive epigenetic scars to reduce long-term MACE risk in these patients.

DOI: https://doi.org/10.1016/j.coph.2026.102664
Front Cell Infect Microbiol. 2026 ;16 1927556

In vitro priming with Mycobacterium fortuitum induces trained immunity-associated phenotypes in caprine alveolar macrophages and enhances phagosomal maturation and antimicrobial functions upon homologous re-stimulation.

Miriam Blay-Benach, Patricia Cuenca-Lara, Julia Moraleda, Zoraida Cervera, Joan Repullés, Bernat Pérez de Val.

   Background: Trained immunity refers to the stimuli-induced epigenetic and metabolic reprogramming of innate immune cells, enabling enhanced non-specific responses upon secondary stimulation. Alveolar macrophages (AMs) constitute the primary immune barrier in the lung and represent a key target in enhancing protection against pulmonary pathogens.
Methods: In this study, an in vitro priming-resting-re-stimulation protocol was used to characterise the ability of Mycobacterium fortuitum (MF) to induce functional features of trained immunity in caprine AMs in vitro. Pro-inflammatory cytokines (TNFα, IL-1β, IL-6) and nitric oxide synthase (iNOS)-positive cells were quantified by multiplex assay and flow cytometry, respectively. Phagosomal acidification was detected by flow cytometry and live-cell fluorescent microscopy after MF-challenge using pH-sensitive labelled bacteria.
Results: MF-trained AMs displayed significantly elevated TNFα and IL-1β production and a higher frequency of inducible iNOS-producing cells compared to non-stimulated controls, consistent with a trained immunity-associated pro-inflammatory and antimicrobial phenotype. Phagosomal acidification was enhanced and sustained in MF-trained AMs following homologous challenge with MF, suggesting enhanced phagocytic activity against mycobacteria.
Conclusion: These findings provide evidence that M. fortuitum induces trained immunity-associated functional responses in caprine AMs and support further trained immunity studies in the caprine lung mucosa against pulmonary infections.

Keywords:  Mycobacterium fortuitum; alveolar macrophages; bactericidal responses; goat; iNOS; macrophage activation; phagocytosis; trained immunity

DOI:  https://doi.org/10.3389/fcimb.2026.1927556
Elife. 2026 Sep 10. pii: RP104977. [Epub ahead of print]14

The C3-C3aR axis modulates trained immunity in alveolar macrophages.

Alexander P Earhart, Alberto E Lopez, Josue I Hernandez, Aasritha Nallapu, Deebly Chavez, Sayahi Suthakaran, Brian Yang, Jungheun Hyun, Rafael Aponte Alburquerque, Marick Starick, Lorena Garnica, Ayse Naz Ozanturk, Rahul Kumar Maurya, Xiaobo Wu, Jeffrey Haspel, Jae Woo Lee, Jaime Hook, Hrishikesh S Kulkarni.

  Complement protein C3 is crucial for immune responses in mucosal sites such as the lung, where it aids in microbe elimination, and enhances inflammation. While trained immunity - enhanced secondary responses of innate immune cells after prior exposure - is well-studied, the role of the complement system in trained immune responses remains unclear. We investigated the role of C3 in trained immunity and found that alveolar macrophage (AM) C3 and C3aR1 expression increased in humans after an intranasal exposure to a training stimulus. In vivo, trained wild-type mice showed significantly elevated proinflammatory cytokines and increased C3a levels upon a second stimulus. Ex vivo, trained C3-deficient AMs displayed reduced chemokine and cytokine output as well as impaired phagocytosis and reactive oxygen species production compared to wild-type AMs. Real-time confocal microscopy of live, intact mouse alveoli revealed that AMs internalize C3 rapidly after alveolar microinstillation, as compared to C3a. Correspondingly, the blunted cytokine output was restored by exogenous C3 but not by C3a. Inhibiting C3aR, both pharmacologically and with a genetic C3aR knockout, prevented this restoration, indicating the necessity of C3aR engagement. Mechanistically, trained WT AMs demonstrated enhanced glycolytic activity compared to C3-deficient AMs - a defect corrected by exogenous C3 in a C3aR-dependent manner. These findings reveal that C3 modulates trained immunity in AMs through C3aR signaling and highlight a novel role for C3 in trained immunity.

Keywords:  Candida; Pseudomonas; alveolar macrophages; complement; human; immunology; immunometabolism; infectious disease; inflammation; microbiology; mouse; training

DOI:  https://doi.org/10.7554/eLife.104977
PLoS Pathog. 2026 Sep 09. 22(9): e1014598

Epigenetic profiling reveals M1 macrophages as the primary drivers of trained immunity in HSV-1 latently infected mice.

Ujjaldeep Jaggi, Shaohui Wang, Homayon Ghiasi.

Macrophages play multifaceted and critical roles in controlling diverse pathogenic infections. Building on our recently published observations of macrophages exhibiting memory responses to HSV-1 infection, our current report investigates the macrophage subtype responsible for generating trained immunity against virus-induced immunopathogenesis. Using ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing), an epigenetic profiling technique, we identified chromatin accessibility changes in both M1 and M2 macrophages associated with the acquisition of IRGM1, a marker of the trained phenotype. To conduct this study, we first generated M0, M1, and M2 macrophage subtypes from bone marrow (BM) derived macrophages isolated from HSV-1 latently infected wild type (WT) mice. ATAC-seq revealed that M1-generated macrophages displayed higher IRGM1-associated chromatin accessibility peaks compared to M2 and M0 subtypes, and this response was enhanced after stimulation with UV-inactivated virus. To further dissect this response, we analyzed memory responses in bone marrow-derived macrophages, spleen macrophages, corneal macrophages, and trigeminal ganglia (TG) of latently infected M1 and M2 macrophages. Flow cytometry and ATAC-seq data showed a significantly higher proportion of IRGM1 ⁺ macrophages in infected M2-/- mice, which are enriched in M1 macrophages. These findings indicate that M1 macrophages, but not M2 macrophages, undergo trained immunity in response to HSV-1 infection. This is also confirmed by the Luminex assay, in which M1 macrophages, after stimulation, then known as primed M1 macrophages, enhance the secretion of pro-inflammatory cytokine/chemokine response to secondary HSV-1 exposure. These results uncover a previously underappreciated role for macrophage-mediated trained immunity in antiviral defense against HSV-1 infection and offer new insights into potential therapeutic targets for modulating host immune responses during HSV-1 infection.

DOI: https://doi.org/10.1371/journal.ppat.1014598
Trends Endocrinol Metab. 2026 Sep 09. pii: S1043-2760(26)00202-X. [Epub ahead of print]

Itaconate.

Eva M Pålsson-McDermott, Luke A J O'Neill.

DOI: https://doi.org/10.1016/j.tem.2026.07.012
J Pharmacol Exp Ther. 2026 Aug 17. pii: S0022-3565(26)01213-9. [Epub ahead of print]393(9): 105013

Prior Toll-like receptor 3 stimulation abolishes the ability of a MAPK/ERK kinase inhibitor to increase lipopolysaccharide-induced nitric oxide production concomitant with tumor necrosis factor-α suppression.

Ryota Hashimoto, Yaojia Wu, Kaily Fujimoto, Haruto Shintani, Hiroshi Koide, Youichi Katoh.

  Lipopolysaccharide (LPS) is an endotoxin that can trigger multiple types of acute organ failure by increasing the production of nitric oxide (NO), which is synthesized by inducible NO synthase (iNOS) in macrophages through increased production of tumor necrosis factor (TNF)-α, interferon gamma, and interleukin-12. We have reported that an inhibitor of MAPK/ERK kinase (MEK), which is activated by LPS, increased the mortality rate in LPS-treated mice through enhanced NO production. However, a strategy to prevent lethal NO production by MEK inhibitors, which are used as anticancer agents, remains unclear. In the present study, we examined whether prestimulation of Toll-like receptors (TLRs) influences NO production by a MEK inhibitor in the presence of LPS because LPS is a ligand of TLR4 and macrophages acquire tolerance through repeated TLR stimulation. The MEK inhibitor increased iNOS expression and NO production in LPS-stimulated mouse macrophages. While pretreatment with TLR3, TLR7/8, or TLR9 agonists abolished the increase in iNOS expression, the subsequent increase in NO production was confirmed to be suppressed by TLR3 stimulation. The MEK inhibitor also suppressed the serum levels of both NO and TNF-α in mice pretreated with the TLR3 agonist poly I:C followed by LPS administration. Both iNOS expression and NO production depended on the TNF-α concentration in mouse macrophages treated with interferon gamma and interleukin-12. These results suggest that the ability of MEK inhibitors to increase NO production in mice treated with LPS is abolished by prior TLR3 stimulation, which is associated with the suppression of TNF-α production. SIGNIFICANCE STATEMENT: A MAPK/ERK kinase inhibitor increased nitric oxide production in lipopolysaccharide-treated mice; however, prior Toll-like receptor 3 stimulation abolished this effect, accompanied by a reduction in tumor necrosis factor-α production. Prior Toll-like receptor 3 stimulation may contribute to a potential strategy to prevent lethal nitric oxide production by MAPK/ERK kinase inhibitors in mice treated with lipopolysaccharide.

Keywords:  Inducible nitric oxide synthase; Lipopolysaccharide; MAPK/ERK kinase inhibitor; Macrophage; Toll-like receptor; Tumor necrosis factor-α

DOI:  https://doi.org/10.1016/j.jpet.2026.105013
Nat Commun. 2026 Aug 08. pii: 9527. [Epub ahead of print]17(1):

Macrophages tune NK cell IFNγ production through direct lipid transfer.

Cathal Keane, Shauna Mayock, Carrie Corkish, Ella Rogerson, Cristhiane Favero de Aguiar, Ya Gao, Sarah Kenny, Lorraine Brennan, Suzanne M Cloonan, David K Finlay.

Natural killer (NK) cells are critical effectors of innate immunity, but their activity is strongly influenced by metabolic state. While intrinsic NK metabolism has been studied extensively, less is known about how surrounding immune cells shape NK cell function. Here, we identify a direct metabolic communication axis between macrophages and NK cells. Using co-culture and in vivo models, we show that lipopolysaccharide-stimulated macrophages induce lipid accumulation in NK cells that suppresses mTORC1 activity and the production of IFNγ. This lipid accumulation is visualised as increased lipid droplets content in NK cells, generated using fatty acids synthesised within the macrophages. Genetic and pharmacological approaches show that fatty acid transfer from macrophages to NK cells requires cell-cell contact and is associated with CD36 protein transfer via trogocytosis. Blocking fatty acid synthesis specifically in macrophages prevents lipid accumulation in NK cells and restores both mTORC1 activity and IFNγ production. These findings define a previously unrecognized mechanism of macrophage-NK cell cross-regulation, revealing how metabolic exchange constrains NK effector function and establishing a feedback circuit with implications for hyperinflammation and immunotherapy.

DOI: https://doi.org/10.1038/s41467-026-76444-0
Adv Sci (Weinh). 2026 Sep 10. e77663

Interleukin-39 is a Prognostic Biomarker and Therapy Target for Sepsis.

Feng-Zhi Zhang, Hai-Jun Liu, Yan Yue, Jun-Jie Gao, Jin Zhang, Wen-Wu Zhang, Yun-Long Zhang, Wei-Hua Lu, Sheng-Wei Jin, Pu-Hong Zhang.

  Sepsis remains a global health crisis with high mortality, due to a paucity of reliable diagnostic markers for accurate risk stratification and precision management. Interleukin-39 (IL-39), a novel immunomodulatory cytokine, plays an important role in regulating the pathophysiology of immunity, metabolism, and et al. Here, we observed significantly elevated serum IL-39 levels in septic patients at admission compared with non-sepsis ICU patients and healthy controls across two independent cohorts. Furthermore, circulating IL-39 concentrations could predict 28-days survival in patients with sepsis. Single-cell sequencing demonstrated that elevated IL-39 was derived from macrophages during sepsis. Meanwhile, supplementation of IL-39, via either recombinant protein (rmIL-39) administration or macrophage-specific AAV-mediated overexpression, profoundly aggravates multiple organ dysfunction and damage in septic mice. Consistently, macrophage IL-39 deficiency, via either macrophage-conditional knockout or macrophage-specific AAV-mediated silence, protects against sepsis. Mechanistically, IL-39 engages GP130 to trigger MAPK/P38 signaling, driving pro-inflammatory cytokine production. Consequently, macrophage-specific GP130 deletion abrogates IL-39-induced sepsis aggravation. Finally, pharmaceutical inhibition of IL-39 with neutralizing antibodies can protect against sepsis. Together, these results highlight the dual clinical utility of IL-39, as both a robust biomarker with independent prognostic value for sepsis patient stratification and a promising therapeutic strategy for sepsis.

Keywords:  GP130; IL‐39; inflammatory factors; macrophage; sepsis

DOI:  https://doi.org/10.1002/advs.77663
Nat Immunol. 2026 Sep 09.

Microbial adhesion promotes Piezo1 activation to initiate innate immunity.

Giulia Stucchi, Marco Galli, Stefano Cozzi, Anna Celant, Laura Marongiu, Giuseppe Rocca, Francesca Colnaghi, Maria Rita Chelazzi, Alessandra Polissi, Alessandra Maria Martorana, Giampiero Pietrocola, Marina Vai, Ivan Orlandi, Renato Ostuni, Simona Barresi, Angelo Lombardo, Metello Innocenti, Francesca Granucci.

How mammals mount an effective immune response against infectious agents remains unresolved. Here we identify microbial adhesion to myeloid cells as a critical initiating event that precedes pattern recognition receptor (PRR) engagement. Using a skin infection model with pathogenic bacteria and fungi, we demonstrate that neutrophil recruitment occurs in two sequential phases. The early phase is PRR-independent and instead driven by microbial adhesion, which engages the mechanosensitive ion channel Piezo1 to promote leukotriene (LT)B4 production. Together with interleukin-1α, LTB4 induces CXCL1 release, triggering neutrophil infiltration via the same circuit at play during sterile inflammation. By contrast, the late phase is toll-like receptor (TLR)- and CXCL2-dependent, marking a transition to the canonical, pathogen-driven response. Our findings uncover microbial adhesion as a previously unrecognized danger signal that activates innate immunity via mechanotransduction, revealing a paradigm of how immune responses to infection are initiated.

DOI: https://doi.org/10.1038/s41590-026-02643-y
Mol Immunol. 2026 Sep 07. pii: S0161-5890(26)00195-1. [Epub ahead of print]199 16-25

β-Glucan alleviates colitis by remodeling the colonic microenvironment and promoting interleukin-33-driven active eosinophil differentiation.

Jun Zhou, Dan Luo, Sujie Hu, Ha Zhu, Zhiqing Li, Likun Cui, Zhou Yu, Xuetao Cao, Chunmei Wang.

  Eosinophils play an essential role in intestinal homeostasis, yet the mechanisms governing their functions in intestine remain poorly defined. β-Glucan, an immunomodulator, has been shown to alleviate colitis, but whether it acts through eosinophils and the underlying mechanisms remains unclear. Here we show that β-Glucan pretreatment significantly attenuated dextran sulfate sodium (DSS)‑induced colitis in wild-type mice but not in eosinophil-deficient mice, indicating an eosinophil-dependent protective effect. β‑Glucan increased the frequency and absolute number of colonic active eosinophils (A-Eos), which correlated with reduced disease severity. Mechanistically, β‑glucan upregulated interleukin-33 (IL‑33) expression in colon tissues. Colon conditioned medium (CM) from β‑glucan‑treated mice directly promoted the differentiation of bone marrow‑derived eosinophils (BM-Eos) into CD80⁺PD‑L1⁺ A‑Eos ex vivo, and this effect was completely reversed by IL-33 neutralization. Our findings identify a novel β-glucan-IL-33-A-Eos axis and provide a mechanistic basis for using β-glucan as an immunomodulatory strategy to prevent inflammatory bowel disease (IBD).

Keywords:  Active eosinophils; Gut microenvironment; Inflammatory bowel disease; Interleukin-33; β-Glucan

DOI:  https://doi.org/10.1016/j.molimm.2026.08.015
JCI Insight. 2026 Sep 08. pii: e199206. [Epub ahead of print]

Previous malaria exposure attenuates monocyte-driven inflammation and correlates with modulation of the B cell response.

Maximilian Julius Lautenbach, Pengjun Xi, Linn Kleberg, Alan-Dine Courey-Ghaouzi, Maia Serene Gower, Carolina Sousa Silva, Felicia Chammas, Anna Färnert, Christopher Sundling.

  Clinical immunity to malaria develops after repeated malaria episodes. In this process, the inflammatory response is modulated to respond less vigorously upon reinfection. Monocytes are a major source of pro-inflammatory mediators during blood-stage infection and are known to adapt to repeated pathogen exposure. Here, we investigated the impact of previous malaria exposure on monocytes during blood-stage malaria by comparing the response in previously exposed and primary infected individuals. We observed reduced levels of several proinflammatory chemokines in previously exposed individuals, linked to changes in monocytes. Similarly, BAFF levels were lower in these individuals and associated with modulation of monocyte and dendritic cells. This affected the BAFF-BAFF-R axis, crucial for B cell responses, correlating with increasing parasite-specific antibody levels. Collectively, we present insights into how previous malaria exposure shapes monocyte responses during acute malaria and how these in turn correlate with modulation of the B cell compartment and humoral immune response. .

Keywords:  Immunology; Infectious disease; Malaria; Monocytes; Tolerance

DOI:  https://doi.org/10.1172/jci.insight.199206
J Inflamm Res. 2026 ;19 629930

To Die or Not to Die: How Sublethal Damage Rewires Cell Fate and Implications for Sepsis.

Zihan Hu, Xing Zhou, Qin Sun, Lianlian Jiang, Mengfan Wu, Jianfeng Xie, Yi Yang, Fei Peng.

  Lytic cell death has long been regarded as an irreversible process culminating in plasma membrane rupture. However, accumulating evidence indicates that the activation of lytic pathways does not invariably result in cell lysis. Instead, cells can undergo sublethal membrane damage, a state in which membrane injury is limited, allowing cells to remain viable while triggering persistent inflammation, barrier dysfunction and other functional alterations. This potentially reversible state may provide a therapeutic window in which limiting membrane rupture or enhancing membrane repair could preserve viable but compromised cells. This review focuses on the three major forms of lytic cell death: pyroptosis, necroptosis, and ferroptosis. We summarize the canonical molecular mechanisms, processes of membrane injury, regulatory pathways, and consequences of sublethal membrane damage. Furthermore, we discuss the shared features and biological impacts of sublethal membrane damage. Given the heterogeneous responses in sepsis, sublethal membrane damage may provide a relevant framework for understanding sepsis pathophysiology. A deeper understanding of this intermediate state may offer novel strategies for sepsis that aim not only to prevent complete cell lysis but also to modulate the function of viable but compromised cells.

Keywords:  ferroptosis; lytic cell death; necroptosis; pyroptosis; sepsis; sublethal membrane damage

DOI:  https://doi.org/10.2147/JIR.S629930