bims-traimu 2025-12-07 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–12–07
nine papers selected by
Yantong Wan, Southern Medical University

Trained immunity and immune priming in plants and invertebrates.
Trained immunity in cardiovascular disease.
The recombinant zoster vaccine induces trained immunity in monocytes through persistent downregulation of TGFβ.
NK cells undergo transcriptional and functional reprogramming following Streptococcus pneumoniae infection.
Propagation of monocyte exhaustion memory and underlying mechanisms.
Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.
Mitochondrial glutathione transporter SLC25A40 regulates macrophage cytokine production.
Single-cell multi-omic landscape reveals anatomical-specific immune features in adult and pediatric sepsis.
NEMO recruitment at single cytokine-receptor complexes shows quantized dynamics independent of ligand affinity.

Elife. 2025 Dec 05. pii: e106597. [Epub ahead of print]14

Trained immunity and immune priming in plants and invertebrates.

Joachim Kurtz, Raul Andino, Diana Boraschi, Jorge Contreras-Garduño, Aardra Kachroo, Imroze Khan, Humberto Lanz Mendoza, Krishnendu Mukherjee, Robert Peuß, Jurriaan Ton.

  Immune memory has long been thought to be restricted to the adaptive immune system of vertebrates. However, several lines of evidence have changed our understanding of immune memory and have shattered the strict separation between innate and adaptive immunity. In vertebrates, a form of innate immunity that is called 'trained immunity' has been intensively studied for over a decade. For more than two decades, studies in plants and an increasing number of invertebrate taxa have clearly demonstrated that these organisms also possess immune memory, despite the absence of an adaptive immune system. These phenomena are mostly known as 'immune priming'. The mechanistic underpinnings of immune priming vary across taxa and may or may not partially include the epigenetic and metabolic mechanisms involved in trained immunity. Here, we offer an evolutionary perspective on immune priming, uniquely integrating key aspects across plants and invertebrates for the first time. As a basis, we provide a conceptual clarification regarding the terms trained immunity and immune priming and give a brief overview of these phenomena across taxa. We then analyze which processes of immune priming share potentially evolutionary conserved epigenetic and metabolic processes with trained immunity and explore signaling processes involved in immune priming. We discuss the aspect of specificity as one of the key defining criteria for immune memory and incorporate the potential role of soil and gut microbiota for acquiring innate immune memory in plants and invertebrates. Finally, we argue that immune priming has enormous potential for application beyond the medical field when involving the protection against parasites and pathogens in agriculture and aquaculture.

Keywords:  evolutionary biology; immune memory; immune priming; innate immunity; invertebrates; plants; trained immunity

DOI:  https://doi.org/10.7554/eLife.106597
Eur Heart J. 2025 Dec 03. pii: ehaf982. [Epub ahead of print]

Trained immunity in cardiovascular disease.

Niels P Riksen, Mihai G Netea, Hafid Ait-Oufella, Triantafyllos Chavakis, George Hajishengallis.

  With innate immunity at the core of the pathophysiology of atherosclerosis, the discovery of new mechanisms of immune cell activation can potentially identify novel pharmacological targets to prevent or treat cardiovascular disease (CVD). One of these mechanisms is trained immunity (TRIM), defined as a recallable long-term hyperinflammatory innate immune phenotype supported by changes of metabolic and epigenetic intracellular processes. TRIM can be induced in mature innate immune cells in tissues, including monocytes/macrophages, and natural killer cells, but also in non-immune cells such as endothelial and epithelial cells (peripheral TRIM). Bone marrow haematopoietic stem and progenitor cells can also be trained (central TRIM), which explains the long-term presence of trained cells, such as monocytes and neutrophils, in the circulation. Recent experimental studies in mice revealed that central TRIM can be induced by traditional CVD risk factors (including diet-induced obesity or intermittent high-fat diet, hyperglycaemia, and hypertension), inflammatory co-morbidities (such as periodontitis and arthritis), unhealthy life-style factors (psychosocial stress and sleep disturbance), and by mechanisms activated by experimental myocardial infarction and stroke. This leads to the long-term presence of hyperinflammatory monocytes and neutrophils that can subsequently accelerate atherosclerosis development. A key mechanism that drives the development of central TRIM in many of these conditions is IL-1β signalling in the bone marrow. In addition, rewiring of cellular metabolism (e.g. activation of glycolysis and glutaminolysis) and changes in histone methylation, acetylation, and lactylation mediate the development of central and peripheral TRIM. We propose that prevention of TRIM by pharmacological targeting of these pathways in myeloid cells represents a new avenue for the prevention and treatment of cardiovascular events.

Keywords:  Atherosclerosis; Cardiovascular disease; Inflammation; Innate immune memory; Monocytes; Trained immunity; Trained innate immunity

DOI:  https://doi.org/10.1093/eurheartj/ehaf982
PLoS Pathog. 2025 Dec 05. 21(12): e1013759

The recombinant zoster vaccine induces trained immunity in monocytes through persistent downregulation of TGFβ.

Michael J Johnson, Megan Crotteau, Debashis Ghosh, Thao Vu, Luke Trinity, Radu Marches, Duygu Ucar, Myron J Levin, Adriana Weinberg.

Older adults have decreased vaccine efficacy, but the adjuvanted recombinant VZV-gE zoster vaccine (RZV) is highly efficacious. We investigated memory-like innate immune responses after RZV and aftrer the zoster vaccine live (ZVL), which is much less efficacious. RZV increased NK, monocyte, and DC activation in response to in vitro VZV-gE stimulation for up to 5 years post-vaccination, while ZVL increased only DC responses to VZV for up to 90 days. In purified monocyte and NK cell cocultures, RZV recipients showed increased responses to VZV-gE, HCMV and HSV antigenic stimulation post-vaccination. ATAC-seq analysis of purified monocytes revealed decreased accessibility in areas of TGFβ1. scRNA-seq and immunoproteomics confirmed decreased TGFβ1 transcription and translation, respectively. Exogenous supplementation and inhibition of TGFβ1 modulated in vitro monocyte responses to VZV-gE. In conclusion, RZV generated homologous (VZV-gE) and heterologous (HCMV, HSV) trained immunity in monocytes through genomic repression of the regulatory cytokine TGFβ-1. Cytokine modulation may represent a novel mechanism of generating trained immunity in myeloid cells.

DOI: https://doi.org/10.1371/journal.ppat.1013759
Mucosal Immunol. 2025 Nov 28. pii: S1933-0219(25)00129-1. [Epub ahead of print]

NK cells undergo transcriptional and functional reprogramming following Streptococcus pneumoniae infection.

Júlia Torné, Claudia Chica, Tiphaine Camarasa, Bernd Jagla, Matilde Enes Dias, Aymeric Zellner, Sébastien Mella, Valentina Libri, Mélanie Anne Hamon.

Natural Killer (NK) cells are cytotoxic lymphocytes and key mediators of innate immunity, essential for combating viral infections and cancer. Notably, they exhibit immunological memory, generating a stronger response upon re-exposure to the same stimulus. While NK cell memory holds promise for infection control, its role in bacterial infections remains poorly understood. Previously, we demonstrated that Streptococcus pneumoniae induces long-term, specific, and protective NK cell memory. In this study, we performed single-cell RNA-seq to uncover how NK cells respond to S. pneumoniae infection. Our findings reveal that challenged Memory (cMemory) NK cells undergo transcriptional reprogramming following S. pneumoniae infection and have a differential transcriptional response upon reinfection. In addition, we identified distinct cMemory NK cell subpopulations, with responding cMemory NK cells displaying a general enhanced activation, proliferation, and cytotoxic activity. These findings support a novel role for NK cells in the context of bacterial infections, thereby opening avenues for harnessing the potential of innate immune memory for therapeutic applications.

DOI: https://doi.org/10.1016/j.mucimm.2025.11.012
Cell Commun Signal. 2025 Dec 05.

Propagation of monocyte exhaustion memory and underlying mechanisms.

Jing Wang, Blake A Caldwell, Yajun Wu, Babak Razani, Liwu Li.

  Monocyte exhaustion is a dysfunctional state characterized by prolonged pathogenic inflammation and immune suppression, commonly observed in chronic infections and sepsis. However, the mechanisms underlying the generation and propagation of exhausted monocytes remain poorly understood. In this study, we investigate the impacts of exhausted monocytes on neighboring naïve monocytes, endothelial cells, and T cell function. Using an in vitro co-culture system, we demonstrate that exhausted monocytes induced by prolonged LPS stimulation propagate the exhaustion phenotype to neighboring naïve monocytes. Meanwhile these exhausted monocytes can promote endothelial apoptosis, upregulate adhesion molecules ICAM-1 and VCAM-1, and enhance monocyte transmigration, contributing to endothelial dysfunction. Pharmacological inhibition of CD38, a key marker of monocyte exhaustion, significantly mitigates these effects, highlighting its critical role in monocyte-driven endothelial alterations. Furthermore, we show that exhausted monocytes suppress T cell proliferation and activation, a process reversed by CD38 inhibition. We also identify mTOR signaling as a key regulator of monocyte exhaustion and its propagation, with mTOR inhibition partially restoring monocyte functionality by downregulating exhaustion markers and STAT1/STAT3/S6K signaling. Collectively, our findings highlight the CD38-mTOR axis as a central driver of monocyte exhaustion and its pathological consequences, offering potential therapeutic targets for reversing immune dysfunction in inflammatory diseases.

Keywords:  CD38; Exhaustion; Monocyte memory dynamics; Propagation; Sepsis

DOI:  https://doi.org/10.1186/s12964-025-02536-x
Cell. 2025 Nov 28. pii: S0092-8674(25)01251-6. [Epub ahead of print]

Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.

Yaqiu Wang, Jianlin Lu, Alexandre F Carisey, Sangappa B Chadchan, Ha Won Lee, R K Subbarao Malireddi, Bhesh Raj Sharma, Nagakannan Pandian, Rebecca E Tweedell, Gustavo Palacios, Nathalie Becerra Mora, Camenzind G Robinson, Aaron Pitre, Peter Vogel, Taosheng Chen, Michael P Murphy, Thirumala-Devi Kanneganti.

  The combination of innate immune activation and metabolic disruption plays critical roles in many diseases, often leading to mitochondrial dysfunction and oxidative stress that drive pathogenesis. However, mechanistic regulation under these conditions remains poorly defined. Here, we report a distinct lytic cell death mechanism induced by innate immune signaling and metabolic disruption, independent of caspase activity and previously described pyroptosis, PANoptosis, necroptosis, ferroptosis, and oxeiptosis. Instead, mitochondria undergoing BAX/BAK1/BID-dependent oxidative stress maintained prolonged plasma membrane contact, leading to local oxidative damage, a process we termed mitoxyperiosis. This process then caused membrane lysis and cell death, termed mitoxyperilysis. mTORC2 regulated the cell death, and mTOR inhibition restored cytoskeletal activity for lamellipodia to retract and mobilize mitochondria away from the membrane, preserving integrity. Activating this pathway in vivo regressed tumors in an mTORC2-dependent manner. Overall, our results identify a lytic cell death modality in response to the synergism of innate immune signaling and metabolic disruption.

Keywords:  carbon starvation; cytokine; inflammasome; inflammatory cell death; innate immunity; mTOR; metabolism; mitochondria; oxidative damage; tumor

DOI:  https://doi.org/10.1016/j.cell.2025.11.002
Sci Rep. 2025 Dec 01. 15(1): 42939

Mitochondrial glutathione transporter SLC25A40 regulates macrophage cytokine production.

Maureen Yin, Eva M Palsson-McDermott, Órlaith C Henry, Ziqian Ge, Juliana E Toller-Kawahisa, Yukun Min, Anne F McGettrick, Adam L Gordon, Stella B Heffernan, Laura Marrone, Bryan P Marzullo, Katherine L Eales, Sally A Clayton, Daniel A Tennant, Richard K Porter, Luke A J O'Neill.

  Mitochondrial glutathione (mtGSH) supports iron-sulfur cluster (ISC) stability in the electron transport chain (ETC). Here we have investigated the role of the mtGSH transporter SLC25A40 in macrophage activation. SLC25A40 is present in both murine and human macrophages and its expression was increased by LPS treatment. Reducing SLC25A40 expression using siRNA destabilized ISC-rich ETC proteins and elevated mitochondrial and cellular reactive oxygen species (ROS). It also induced expression of the genes Gclc and Gclm, which are involved in GSH biosynthesis. SLC25A40 deficiency also diminished IL-1β and IL-10 production at the transcriptional level in response to LPS. As a result, the production of mature IL-1β was decreased following activation of NLRP3 by nigericin or ATP, with no effect on pyroptosis. Depleting mtGSH with mitochondrially-targeted CDNB phenocopied these defects, whereas supplementation with a cell-permeable GSH ester partially restored pro-IL-1β production. Together, these data identify SLC25A40 as a key regulator that sustains ETC integrity to promote cytokine production, revealing a previously unrecognized role for the SLC25A40-mtGSH axis in coupling mitochondrial redox control to macrophage activation.

Keywords:  Cytokine; Electron transport chain (ETC); Glutathione (GSH); Macrophage immunometabolism; Mitochondria; SLC25A39/40

DOI:  https://doi.org/10.1038/s41598-025-30333-6
Nat Immunol. 2025 Dec 03.

Single-cell multi-omic landscape reveals anatomical-specific immune features in adult and pediatric sepsis.

Qian Ye, Xiaofei Lai, Yuliang Liu, Zhengtao Zhang, Yueqiang Fu, Jie Luo, Chengjun Liu, Jun Duan, Hao Ding, Yuhan Liu, Zhi Ao, Yang Tao, Shanmu Ai, Wei Huang, Lei Jiang, Yi Liu, Fang Xu, Ju Cao.

The anatomical source of infection is a major determinant of sepsis outcomes; however, how distinct sites shape immunity remains unclear. Here we applied multi-omic profiling, integrating single-cell transcriptomics, single-cell T cell receptor and B cell receptor sequencing, CITE-seq, bulk RNA sequencing and plasma proteomics, to analyze peripheral blood mononuclear cells and plasma from 281 adult and pediatric individuals with sepsis and controls. We identified an NR4A2+ central memory CD4+ T cell subset enriched in abdominal, pulmonary and skin sepsis, with features of exhaustion; genetic perturbations showed Nr4a2 loss improved survival, while overexpression worsened it. Proinflammatory CD8+ T, natural killer and natural killer T subsets expressing CCL4, CCL3 and tumor necrosis factor expanded in adult abdominal and pulmonary sepsis, while pediatric pulmonary sepsis featured proliferative CD14+ monocytes, findings validated in external single-cell cohorts and confirmed in 164 independent individuals. Plasma proteomics revealed shared mediators including interleukin-6 and EN-RAGE across anatomical sites and ages. Together, our findings delineate anatomical-specific and age-specific immune programs in sepsis, highlighting candidate targets for precision immunotherapy.

DOI: https://doi.org/10.1038/s41590-025-02345-x
Cell Rep. 2025 Dec 02. pii: S2211-1247(25)01409-3. [Epub ahead of print]44(12): 116637

NEMO recruitment at single cytokine-receptor complexes shows quantized dynamics independent of ligand affinity.

A Hyun Kim, Benjamin Krummenacher, Jason Yeung, David R Koes, Robin E C Lee.

  Cells use a limited number of receptors to sense and process molecular information from their environment. In the classical view of signaling, receptor-ligand affinities determine binding kinetics, on timescales of diffusion, where their time-averaged contact duration regulates rapid cytoplasmic signaling events to coordinate cellular responses. For some cytokines, single receptor-ligand binding events can initiate large multiprotein complexes in the cytoplasm that assemble over tens of minutes, raising the question of how cytokine affinity influences the sensitivity and strength of signaling. Here, we leverage naturally occurring variations of interleukin (IL)-1β from multiple species to determine the impact of affinity on human IL-1 receptor signaling. Using experiments and models, we investigate single receptor complexes activated by ligands that vary across multiple orders of magnitude in affinity. Our results show that while the receptor-ligand affinity establishes cytokine response sensitivity, activated IL-1 receptor complexes signal as discrete, quantized packets of signaling flux independent of affinity.

Keywords:  CP: cell biology; CP: molecular biology; IL-1β; Il-1R1; affinity; cross-species protein interaction; cytokine structure; live-cell imaging; receptor signaling; signal quantization; single particle tracking

DOI:  https://doi.org/10.1016/j.celrep.2025.116637