bims-traimu 2025-11-23 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–11–23
thirteen papers selected by
Yantong Wan, Southern Medical University

Can Nuclear Imaging Detect Trained Immunity in Cardiovascular Disease?
Trained Immunity Exacerbates Inflammatory Arthritis Progression via Promoting Synovial Fibroblast Ferroptotic Resistance.
Cutibacterium acnes induces skin region-specific innate immune memory alterations in human keratinocytes.
NLRP3-mediated trained immunity of microglia is involved in the recurrence-like episode of depressive disorders.
Exposure to bacterial lipopolysaccharide aggravates H1N1-mediated lung immunopathology via neutrophil extracellular trap formation.
The immunoproteasome regulates ILC2 responses by modulating mitochondrial capacity.
The NLRP6 inflammasome is activated by sterile or pathogen-induced endolysosomal damage.
Targeting plasticity in the pyrimidine synthesis pathway potentiates macrophage-mediated phagocytosis in pancreatic cancer models.
Homeostatic control of energy metabolism by monocyte-derived macrophages.
Persistent memory in network topologies following temporary stimuli.
Modulation function of sphingomyelin molecular species in TLR4 signaling and cell death.
Single-Cell Insights Into Macrophage Subtypes in Pulmonary Infections.
RIOK2 kinase regulates the translocation of the FADD-RIPK1-Caspase-8 complex to the ER and the cleavage of Gasdermin D to drive pyroptosis.

Arterioscler Thromb Vasc Biol. 2025 Nov 20.

Can Nuclear Imaging Detect Trained Immunity in Cardiovascular Disease?

Abraham J P Teunissen, Mandy M T van Leent.

  Inflammation is a major driver of atherosclerotic cardiovascular disease, and the key roles of trained immunity in initiating and driving this condition are increasingly recognized. However, monitoring trained immunity in patients, particularly inside the atherosclerotic plaque, remains challenging due to a lack of noninvasive readouts. Here, we discuss the potential of nuclear imaging in studying trained immunity in atherosclerotic cardiovascular disease. We show that many trained immunity-relevant radiotracers exist, including ones targeting innate immune cells, metabolic processes, and epigenetic enzymes. However, their use remains limited, and distinguishing trained immunity from other immune processes remains challenging, highlighting the need for more specific trained immunity biomarkers.

Keywords:  atherosclerosis; biomarkers; cardiovascular diseases; inflammation; trained immunity

DOI:  https://doi.org/10.1161/ATVBAHA.125.322613
Adv Sci (Weinh). 2025 Nov 19. e04245

Trained Immunity Exacerbates Inflammatory Arthritis Progression via Promoting Synovial Fibroblast Ferroptotic Resistance.

Haibo Su, Baoying Zhang, Qiudi Deng, Jiaxin Huang, Jinyu Feng, Yuan Fu, Yuejun Huang, Weikun Deng, YingJun Su, Huisheng Liu, Ning-Yi Shao, Zhenhui Zhang, Jianwei Dai.

  Trained immunity induced by β-glucan insult drives the functional reprogramming of macrophages to the hyperinflammatory status, contributing to developing or maintaining inflammatory diseases. Inflammatory arthritis is characterized by an idiopathically hyperinflammatory response, a phenotype similar to that of trained immunity, and its etiology involves environmental factors such as β-glucan exposure. However, whether trained immunity contributes to inflammatory arthritis progression, as well as the reciprocal interactions, remains elusive. The study shows that β-glucan-induced experimental trained immunity heighten inflammation and arthritis severity in collagen-induced arthritis (CIA) rat model. Trained macrophages by β-glucan, upon adoptive transfer, further intensify symptoms. In arthritis progression, trained macrophages reduce fibroblast-like synoviocytes' (FLS) lipid peroxidation, lessening sensitivity to iFSP1-induced ferroptosis through interleukin-1 beta (IL-1β)/N-acetyltransferase 10 (NAT10)/ferroptosis suppressor protein 1 (FSP1) mRNA ac4C modification. A therapeutic approach targeting trained immunity, combining low-dose iFSP1 and Remodelin, mitigates arthritis severity and restores ferroptosis sensitivity. Additionally, this interplay between CIA induction and β-glucan training creates a feedback loop reinforcing trained immune memory, accelerating disease deterioration. The findings highlight trained immunity induced by endogenous or exogenous insult, such as β-glucan, as an unexplored mechanism of inflammation dysregulation in the pathogenesis of inflammatory arthritis, opening avenues for the therapeutic approaches by targeting trained immunity.

Keywords:  ferroptosis; inflammatory arthritis; innate immune memory; trained immunity; trained macrophages

DOI:  https://doi.org/10.1002/advs.202504245
J Invest Dermatol. 2025 Nov 14. pii: S0022-202X(25)03544-4. [Epub ahead of print]

Cutibacterium acnes induces skin region-specific innate immune memory alterations in human keratinocytes.

Fanni Balogh, Anett Magyari, Lilla Erdei, Beáta Szilvia Bolla, Balázs Koncz, Laura Bagi, Máté Manczinger, Blanka Toldi, Bálint Baráth, Katalin Burián, Rolland Gyulai, Lajos Kemény, Kornélia Szabó.

  External insults can cause immune activation in immune cells, resulting in persistent molecular changes that can lead to innate immune memory (IIM) changes in these cells. This study investigated the potential for cellular reprogramming in response to Cutibacterium acnes in keratinocytes. We exposed normal human epidermal keratinocytes obtained by mammoplasty (NHEK-B) or abdominoplasty (NHEK-A) to C. acnes, followed by stimulation with Pam3CSK4 to assess immune activation and cellular responses. In NHEK-B cells, C. acnes and Pam3CSK4 treatment induced trained immunity-type responses, higher expression of selected immune target genes, and a diminished response compared with trained and Pam3CSK4-induced NHEK-A cells. Total transcriptome analysis delineated regional differences, with the activation of immune-related pathways in NHEK-B cells and alterations in keratinocyte differentiation processes in NHEK-A cells. We detected differences in metabolic regulation, and utilizing pharmacological inhibitors, we demonstrated the necessity of the optimal regulation of histone acetylation and DNA methylation for the aforementioned changes. This study demonstrated that C. acnes triggers IIM processes in keratinocytes, characterized by signaling, epigenetic, and metabolic reprogramming that influences cellular responses to subsequent stimuli. The observation that analogous insults might elicit skin region-specific responses offers insights into the etiology and mechanisms underlying common inflammatory skin diseases.

Keywords:  Cutibacterium acnes; epigenetics; innate immune; innate immune memory; microbiota

DOI:  https://doi.org/10.1016/j.jid.2025.10.610
Mol Psychiatry. 2025 Nov 18.

NLRP3-mediated trained immunity of microglia is involved in the recurrence-like episode of depressive disorders.

Gaojie Xu, Minlan Yuan, Hui He, Jin Yi, Xinyu Li, Hao Yan, Gangcai Liu, Ziqiang Wu, Xiaomei Zhang, Yuxiang Chen, Shanyu Lin, Qian Yang, Jinqiang Zhang, Michael Maes, Wei Zhang, Huafu Chen, Zili You.

Recurrent major depression is associated with increased morbidity, suicidal behaviors and increasing neurocognitive deficits. Microglia-mediated neuroinflammatory processes deeply participate in the physiopathology of depression. In response to stress, microglia can develop trained immunity mediated by epigenetic reprogramming, which can enhance the neuro-inflammatory response to subsequent insults. Here, we investigate whether, in animal models, previous depressive-like behaviors are associated with microglial trained immunity, which increases the susceptibility of mice to stress, resulting in the reocurrence of depressive-like behaviors. In the hippocampus and after recovery of initial chronic mild stress (CMS)-induced depressive behaviors, this study discovered increased and persistent chromatin accessibility and H3K4me3 marks in genes related to proinflammatory response, but without sustaining microglial activation and neuroinflammation. Furthermore, the initial CMS induced increased H3K4me3 deposition on the promotor region of NLRP3, inducing impairments in the adult hippocampal neurogenesis and stress sensitization when mice are re-exposed to subthreshold stress (reCMS) for 2 weeks, resulting in the reocurrence of depressive-like behaviors, which could be reversed through specific knockdown of NLRP3 in hippocampal microglia. Blockade of H3K4me3-mediated NLRP3 activation via the H3K4me3 inhibitor rescued neurogenesis impairment induced by initial CMS, and ameliorated the enhanced susceptibility of mice to stress re-exposure. Collectively, initial CMS induced a NLRP3-dependent trained immunity of microglia, which was mediated by epigenetic reprogramming, facilitating the susceptibility of mice to subsequent stress, thereby contributing to the reocurrence of depressive-like behaviors. Our findings might provide a perspective strategy for the prevention and treatment of depression recurrence.

DOI: https://doi.org/10.1038/s41380-025-03344-y
Sci Rep. 2025 Nov 18. 15(1): 40541

Exposure to bacterial lipopolysaccharide aggravates H1N1-mediated lung immunopathology via neutrophil extracellular trap formation.

Guiling Yan, Zhongwen Hu, Yuanyuan Peng, Yuqin Tu, Jingling Xie, Yuchao Zhong, Changchun Niu, Yang Luo.

  Influenza A virus (IAV) is a prevalent pathogen that causes severe respiratory infections worldwide. Currently, the incidence of coinfections between IAV and Gram-negative bacteria has been steadily increasing, and the synergistic interaction between IAV infection and bacterial exposure represents a pivotal risk factor for disease exacerbation. Lipopolysaccharide (LPS), a major Gram-negative bacterial virulence factor, is hypothesized to regulate IAV-induced immune response intensity and disease severity by reshaping the pulmonary immune microenvironment. Here, we established an in vivo coadministration model via intratracheal instillation of low-dose LPS and H1N1 to dissect their synergistic pathogenesis. LPS exposure potentiated H1N1-induced severe lung injury, manifested as persistent neutrophil and monocyte infiltration, elevated levels of cytokines (e.g., CXCL1, CCL2, and IL-6), and alveolar damage without affecting viral replication. Mechanistically, LPS triggered immune hyperactivation through early neutrophil recruitment, neutrophil extracellular trap (NET) formation, and a self-sustaining positive feedback loop. Intervention experiments revealed that the degradation of NETs by DNase I or neutrophil inhibition significantly alleviated lung damage and systemic inflammatory responses. This study establishes NET-driven innate immune amplification as a key mechanism underlying LPS-enhanced H1N1 pathogenicity, offers an immunomodulatory approach for severe bacterial-viral coinfections, and underscores the parity of immunomodulatory therapy with anti-infective treatment.

Keywords:  Bacteria; Inflammatory cytokines; Influenza; Neutrophil extracellular traps; Synergistic effects

DOI:  https://doi.org/10.1038/s41598-025-24349-1
Proc Natl Acad Sci U S A. 2025 Nov 25. 122(47): e2518190122

The immunoproteasome regulates ILC2 responses by modulating mitochondrial capacity.

Paôline Laurent, Vidyanath Chaudhary, Daqiang Li, Marie Dominique Ah Kioon, Chen Zhang, William H Miller, Hua Liao, Gang Lin, Carl F Nathan, Franck J Barrat.

  Type 2 innate lymphoid cells (ILC2s) contribute to type 2 immunity but have also been associated with multiple inflammatory diseases, including airway inflammation and asthma. We report that beyond its function of degrading poly-ubiquitinylated proteins, the immunoproteasome (i-20S) is required for the proper function of ILC2s by controlling their mitochondrial capacity. We found that 90% of the catalytic β subunits of proteasomes in human ILC2s (hILC2s) are the immuno- (β5i) rather than constitutive (β5c) isoform. Specific, noncovalent, reversible inhibition of i-20S β5i (LMP7) in hILC2s induced ROS production, which inhibited aconitase, leading to altered mitochondrial function and reduced levels of ATP. Reprogramming of metabolic status by an LMP7 inhibitor impaired ILC2 activation, without significant cytotoxicity or preventing their recovery. Hence, the selective inhibition of i-20S in ILC2 cells did not kill them but reversibly depleted their ATP, preventing their activation and cytokine secretion. In mice, proteasome inhibition similarly blocked mitochondrial function and ILC2 activation, preventing airway inflammation in response to IL33 and asthma in response to house dust mites. These findings reveal a previously unappreciated linkage between proteasome blockade, central carbon metabolism, and mitochondrial function and identify a strategy to regulate immune cell metabolism in inflammatory diseases.

Keywords:  airway inflammation; innate lymphoid cells; metabolism; proteasome

DOI:  https://doi.org/10.1073/pnas.2518190122
EMBO J. 2025 Nov 20.

The NLRP6 inflammasome is activated by sterile or pathogen-induced endolysosomal damage.

Alexandra Boegli, Elliott M Bernard, Louise Lacante, Gaël Majeux, Ella Hartenian, Vanessa Mack, Petr Broz.

  The cytosolic innate immune sensor NLRP6 controls host defense against bacteria and viruses in the gastrointestinal tract, but the underlying mechanism is poorly understood. Here, we report that NLRP6 forms an inflammasome following endolysosomal damage caused by sterile triggers or bacterial pathogens such as Listeria monocytogenes in human intestinal epithelial cells (IECs). NLRP6 activation requires Listeriolysin O-dependent cytosolic invasion of L. monocytogenes and triggers IEC pyroptosis and IL-1β release via ASC/caspase-1-mediated GSDMD cleavage. NLRP6 activation requires its NACHT domain and ATP binding, whereas inflammasome formation is independent of bacterial pathogen-associated molecular patterns (PAMPs), such as lipoteichoic acid or dsRNA, which were previously reported to activate NLRP6. L. monocytogenes mutants deficient in cell-to-cell spread or escape from secondary vacuoles induce lower levels of cell death, linking bacteria-induced endolysosomal damage to NLRP6 activation. Finally, sterile endolysosomal damage recapitulates pathogen-induced NLRP6 activation and induces IEC pyroptosis. In summary, our study reveals that NLRP6 enables intestinal epithelial cells to detect endolysosomal damage, thereby mediating their response not only to pathogens but more generally to wide-ranging sources of pathological endolysosomal damage.

Keywords:  Endolysosomal Damage; Inflammasome; Listeria; NLRP6; Pyroptosis

DOI:  https://doi.org/10.1038/s44318-025-00637-4
J Clin Invest. 2025 Nov 17. pii: e193370. [Epub ahead of print]135(22):

Targeting plasticity in the pyrimidine synthesis pathway potentiates macrophage-mediated phagocytosis in pancreatic cancer models.

Jie Zhao, Xinghao Li, Xinyu Li, Pengfei Ren, Yilan Wu, Hao Gong, Lijian Wu, Junran Huang, Saisai Wang, Ziwei Guo, Mo Chen, Zexian Zeng, Deng Pan.

  Macrophage-mediated phagocytosis plays a critical role in the elimination of cancer cells and shaping antitumor immunity. However, the tumor-intrinsic pathways that regulate cancer cell sensitivity to macrophage-mediated phagocytosis remain poorly defined. In this study, we performed a genome-wide CRISPR screen in murine pancreatic cancer cells cocultured with primary macrophages and identified that disruption of the tumor-intrinsic pyrimidine synthesis pathway enhances phagocytosis. Mechanistically, we discovered that macrophages inhibit the pyrimidine salvage pathway in tumor cells by upregulating Upp1-mediated uridine degradation through cytokines TNF-α and IL-1. This shift increased tumor cells' reliance on de novo pyrimidine synthesis. As a result, tumor cells with impaired de novo pyrimidine synthesis showed depleted UMP and displayed enhanced exposure of phosphatidylserine (PtdSer), a major "eat-me" signal, thereby promoting macrophage-mediated phagocytosis. In multiple pancreatic cancer models, Cad-deficient tumors exhibited markedly reduced tumor burden with increased levels of phagocytosis by macrophages. Importantly, the Cad-mediated suppression of pancreatic cancer was dependent on TAMs and cytokines IL-1 and TNF-α. Pharmacological inhibition of DHODH, which blocks de novo pyrimidine synthesis, similarly decreased tumor burden with enhanced phagocytosis in pancreatic cancer models. These findings highlight the critical role of the tumor-intrinsic pyrimidine synthesis pathway in modulating macrophage-mediated antitumor immunity, with potential therapeutic implications.

Keywords:  Cancer immunotherapy; Immunology; Innate immunity; Macrophages; Metabolism; Oncology

DOI:  https://doi.org/10.1172/JCI193370
EMBO J. 2025 Nov 17.

Homeostatic control of energy metabolism by monocyte-derived macrophages.

Rui Martins, Birte Blankehaus, Faouzi Braza, Miguel Mesquita, Pedro Ventura, Sumnima Singh, Sebastian Weis, Maria Pires, Sara Pagnotta, Qian Wu, Sílvia Cardoso, Elisa Jentho, Ana Figueiredo, Pedro Faísca, Ana Nóvoa, Vanessa Alexandra Morais, Stefanie K Wculek, David Sancho, Moises Mallo, Miguel P Soares.

  Multicellular organisms rely on inter-organ communication networks to maintain vital parameters within a dynamic physiological range. Macrophages are central to this homeostatic control system, sensing and responding to deviations of those parameters to sustain organismal homeostasis. Here, we demonstrate that dysregulation of iron (Fe) metabolism, imposed by the deletion of ferritin H chain (FTH) in mouse parenchymal cells, is sensed by monocyte-derived macrophages. In response, monocyte-derived macrophages support tissue function, energy metabolism, and thermoregulation via a mechanism that sustains the mitochondria of parenchymal cells. Mechanistically, FTH supports a transcriptional program promoting mitochondrial biogenesis in macrophages, involving mitochondrial transcription factor A (TFAM). Moreover, FTH sustains macrophage viability and supports intercellular mitochondrial transfer from donor parenchymal cells. In conclusion, monocyte-derived macrophages cross-regulate iron and energy metabolism to support tissue function and organismal homeostasis.

Keywords:  Ferritin; Homeostasis; Macrophages; Metabolism; Mitochondria

DOI:  https://doi.org/10.1038/s44318-025-00622-x
iScience. 2025 Nov 21. 28(11): 113765

Persistent memory in network topologies following temporary stimuli.

Federico Sevlever, Ariel Waisman, Santiago Miriuka, Alejandra C Ventura.

  Molecular memory in signaling and gene regulatory networks shapes how cells respond to transient inputs. Here, we present a mathematical framework to quantify memory as changes in system state after temporary stimulation. Using computational models, we show that circuits with positive feedback loops, particularly those enabling bistability, sustain long-term memory, while certain negative feedbacks can erase it. We further identify minimal network motifs that reliably confer memory, revealing symmetry between activating and inactivating mechanisms. In addition, oscillatory circuits can encode memory even without positive feedback, storing information in the phase of their oscillations. Applying this approach to mouse embryonic stem cells exposed to transient differentiation cues, we find that different genes display distinct degrees of memory retention, with some reflecting partial reversion and others indicating commitment to differentiation. This framework provides a unified way to compare memory across systems and highlights how circuit architecture influences information storage in biology.

Keywords:  Bioinformatics; Computermodeling; Systems biology

DOI:  https://doi.org/10.1016/j.isci.2025.113765
Cell Rep. 2025 Nov 18. pii: S2211-1247(25)01340-3. [Epub ahead of print]44(12): 116568

Modulation function of sphingomyelin molecular species in TLR4 signaling and cell death.

Xuhao Huang, Hirotaka Kanoh, Jumpei Ueno, Ushio Ishikawa, Takahiro Nitta, Masayuki Takamatsu, Atsushi Shimoyama, Makoto Taniguchi, Shinya Hanashima, Kei-Ichiro Inamori, Jin-Ichi Inokuchi, Koichi Fukase, Kazuya Kabayama.

  The innate immune system provides the first line of defense against pathogens. However, the mechanisms underlying its endogenous regulation remain unclear. We identified sphingomyelin (SM) as a novel immunomodulatory ligand. SM in serum consists of various fatty acid species. Our findings reveal that SM species regulate inflammatory cell death and cytokine release in an acyl-chain-dependent manner via Toll-like receptor 4 (TLR4)-myeloid differentiation factor-2 (MD-2) signaling. Specifically, N-lauroyl-D-erythro-sphingosylphosphorylcholine (SM C12) and N-myristoyl-D-erythro-sphingosylphosphorylcholine (SM C14) induce inflammatory cell death and pyroptosis in mouse macrophages. The activation of human caspase-4, mouse caspase-11, and gasdermin D underlies this pyroptotic response, and we have identified SM C12 as a ligand for caspase-4. Our results suggest a dual role for SM in mediating inflammation or suppressing LPS-stimulated inflammation through both cell surface TLR4/MD-2 interaction and intracellular caspase signaling pathways. This newfound understanding of SM's immunomodulatory properties opens avenues for exploring its therapeutic potential in modulating innate immune responses.

Keywords:  CP: immunology; TLR4; cell death; inflammation; innate immunity; sphingomyelin

DOI:  https://doi.org/10.1016/j.celrep.2025.116568
Adv Sci (Weinh). 2025 Nov 21. e10758

Single-Cell Insights Into Macrophage Subtypes in Pulmonary Infections.

Zhaoheng Lin, Yuxiao Zheng, Yu Zhong, Hongyan Wang.

  Macrophages are pivotal innate immune cells that play essential roles in pathogen recognition, inflammation modulation, and tissue repair during pulmonary infections. Macrophages have remarkable plasticity that is shaped by diverse external stimuli to adapt to the dynamic lung microenvironment. Traditional models of macrophage polarization (M1/M2) cannot capture the full complexity of macrophage heterogeneity and diverse functions during lung infections. Recent advances in single-cell omics have provided new insights into distinct macrophage subtypes, revealing their unique transcriptional profiles across various stages of infection. This review focuses on the functional plasticity of pulmonary macrophages and how environmental cues modulate their activation and effector functions. An integrative classification framework that defines six major functional macrophage subtypes in pulmonary infections, based on single-cell omics with functional perspectives is proposed. This framework refines the understanding of macrophage heterogeneity and offers a foundation for developing targeted immunotherapeutic strategies against lung infections.

Keywords:  cell fate plasticity; macrophage subtypes; pulmonary infections; single‐cell omics

DOI:  https://doi.org/10.1002/advs.202510758
Nat Commun. 2025 Nov 17. 16(1): 10060

RIOK2 kinase regulates the translocation of the FADD-RIPK1-Caspase-8 complex to the ER and the cleavage of Gasdermin D to drive pyroptosis.

Mingtong Ma, Fei Wang, Pengfei Cui, Yingying Zhang, Hanyu Ma, Yifan He, Yuanna Cheng, Jingping Huang, Jingxiang Wang, Xiangyang Wu, Hua Yang, Ruijuan Zheng, Haowen Ma, Qian Cai, Lin Wang, Baoxue Ge.

Macrophage infection by the pathogenic bacteria Yersinia or mimic stimulation of lipopolysaccharide (LPS) and transforming growth factor-β-activated kinase 1 (TAK1) inhibitor or tumor necrosis factor (TNF) and TAK1 inhibitor induces caspase-8-mediated gasdermin D (GSDMD) cleavage and pyroptosis. However, the upstream regulator of caspase-8-dependent cleavage of GSDMD remains elusive. Here we show that Serine/threonine-protein kinase RIO2 (RIOK2) interacts with the Fas-associated protein with death domain (FADD) and is essential for caspase-8-driven GSDMD cleavage. RIOK2's kinase activity drives the transport of lysosome to ER through activating myosin II and thereby translocate FADD-RIPK1-caspase-8 complex from lysosome to ER. Importantly, RIOK2's ATPase activity enhances its binding to this complex and directly triggers caspase-8 and gasdermin D cleavage both at ER and in vitro. Furthermore, RIOK2-mediated pyroptosis enhances host defense against Yersinia infection. Thus, our findings define an upstream regulator of caspase-8-dependent pyroptosis, implying a role of organelle crosstalk in spatial cleavage of gasdermins.

DOI: https://doi.org/10.1038/s41467-025-65012-7