bims-traimu 2025-08-17 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–08–17
sixteen papers selected by
Yantong Wan, Southern Medical University

Metabolic imprinting drives epithelial memory during mucosal fungal infection.
Long-term effects of BCG vaccination on telomere length and telomerase activity.
Constraints and tunability of antigen-agnostic memory durability.
Protocol for measuring endogenous 24(S),25-epoxycholesterol and inducing innate immune memory in mouse macrophages.
[Normal and emergency hematopoiesis: current concepts and clinical implications].
Ulcerative Colitis Aggravates Periodontitis via Inducing Myelopoiesis.
Coptisine Improves Liver Inflammation in Sepsis by Regulating STAT1/IRF1/GPX4 Signaling-Mediated Kupffer Cells Ferroptosis.
Trained human bone marrow mesenchymal stem cells restore tissue immuno-microenvironment in fulminant hepatic failure mice.
Astrocyte priming enhances microglial Aβ clearance and is compromised by APOE4.
The ghost of infections past: Accounting for heterogeneity in individual infection history improves accuracy in epidemic forecasting.
Integrated time-series analysis and high-content CRISPR screening delineate the dynamics of macrophage immune regulation.
A citrullinated histone H3 monoclonal antibody for immune modulation in sepsis.
Tumor Extracellular Vesicles Aggravate Mitochondrial Damage in Myocardial Ischemia/Reperfusion Injury.
Individual subsets of alternatively-activated macrophages differentially contribute to tissue repair and the resolution of inflammation.
Succinate preserves CD8+ T cell fitness to augment antitumor immunity.
Biologically Active Implants Prevent Mortality in a Mouse Sepsis Model.

bioRxiv. 2025 Jul 17. pii: 2025.07.11.664387. [Epub ahead of print]

Metabolic imprinting drives epithelial memory during mucosal fungal infection.

Jinendiran Sekar, Norma V Solis, Jian Miao, Nicolas Millet, Bryce Tom, Derek Quintanilla, Aize Pellon, David L Moyes, Joseph A Gogos, Harry B Rossiter, Scott G Filler, Mihai G Netea, Jennifer K Yee, Marc Swidergall.

Epithelial cells at barrier sites are emerging as active participants in innate immune memory, yet the underlying metabolic and epigenetic mechanisms remain unclear. Here, we uncover a previously unrecognized form of trained immunity in oral epithelial cells that enhances protection against fungal infection. Using a mouse model, we show that mucosal exposure to Candida albicans confers sustained protective memory that is independent of adaptive immunity and myeloid cells. Mechanistically, mucosal memory is driven by proline catabolism via proline dehydrogenase (Prodh) in epithelial cells, which sustains mitochondrial function, epigenetic remodeling, and promotes cytokine production upon secondary challenge. Unlike classical trained immunity in immune cells, epithelial memory is independent of glycolysis but partially sustained by fatty acid oxidation via carnitine palmitoyltransferase-I (CPT1). These findings uncover a distinct metabolic-epigenetic axis that underlines long-term epithelial memory in the oral mucosa and reveal novel non-hematopoietic mechanisms of mucosal defense against fungal pathogens.

DOI: https://doi.org/10.1101/2025.07.11.664387
iScience. 2025 Aug 15. 28(8): 113159

Long-term effects of BCG vaccination on telomere length and telomerase activity.

Ozlem Bulut, Valerie A C M Koeken, Simone J C F M Moorlag, Charlotte J de Bree, Vera P Mourits, Gizem Kilic, Priya A Debisarun, Marijke P A Baltissen, Joost H A Martens, Jorge Domínguez-Andrés, Leo A B Joosten, Mihai G Netea.

  This study explores the effects of Bacillus Calmette-Guérin (BCG) vaccination on telomere maintenance, an aging-related process, in immune cells. While BCG reduces systemic inflammation and enhances innate immune responsiveness by inducing trained immunity, its effects on other immune aging hallmarks, such as telomere shortening, are not fully understood. We assessed telomere length in two independent human cohorts before and three months after BCG vaccination. Telomere shortening was consistently observed after BCG, but not after placebo vaccination. Trained immunity non-responders were likelier to lose telomere length, but only among males. Higher pre-vaccination testosterone levels were associated with greater telomere loss in males. In vitro, BCG training activated telomerase, particularly in females, and this was partially prevented by exogenous testosterone. These findings suggest BCG vaccination influences telomere dynamics in a sex-specific manner, contributing to understanding BCG's broader effects on aging-related processes.

Keywords:  Age; Cell biology; Immunology

DOI:  https://doi.org/10.1016/j.isci.2025.113159
bioRxiv. 2025 Jul 19. pii: 2025.07.18.663399. [Epub ahead of print]

Constraints and tunability of antigen-agnostic memory durability.

Shubham Tripathi, Can Liu, William W Lau, Rachel Sparks, John S Tsang.

Apart from antigen-specific immune memory, infection or vaccination can also induce antigen-agnostic memory including bystander T cell activation memory and trained innate immunity. Determinants of the durability of such memory remain unclear. We developed mathematical models to show that antigen-agnostic memory durability is constrained by immune cell turnover and cytokine dependence. Trained immunity durability is further constrained by the fidelity of epigenetic state transmission during self-renewal and differentiation. Using computer simulations and a machine learning-based parameter-phenotype mapping approach, we find that positive feedback mediated by immune cell-secreted cytokines, a motif seen across immune circuits, can lead to tunable memory involving excitable responses to acute challenges followed by slow relaxation to the pre-challenge baseline. We propose specific experiments to test predictions from our models. Our findings thus reveal a cell extrinsic mechanism that can overcome the constraints imposed by cell turnover and epigenetic state transmission to drive long-lasting, tunable antigen-agnostic memory.

DOI: https://doi.org/10.1101/2025.07.18.663399
STAR Protoc. 2025 Aug 09. pii: S2666-1667(25)00430-7. [Epub ahead of print]6(3): 104024

Protocol for measuring endogenous 24(S),25-epoxycholesterol and inducing innate immune memory in mouse macrophages.

Yongxiang Liu, Huan Jin, Bitao Huo, Xiaojun Xia, Jinyun Liu.

  Multiple metabolic pathways and metabolites are involved in innate immune memory induction of macrophages; however, protocols for in vitro-trained immunity assays induced by metabolites in mouse macrophages are limited. Here, we present a protocol for measuring endogenous 24(S),25-epoxycholesterol and inducing innate immune memory in mouse macrophages. We describe steps for sample preparation, measurement of 24(S),25-epoxycholesterol, and establishment of an in vitro-trained immunity model. We then detail procedures for assays measuring cytokine concentration and for assay for transposase-accessible chromatin using sequencing (ATAC-seq). For complete details on the use and execution of this protocol, please refer to Liu et al.1.

Keywords:  Cell Biology; Immunology; Metabolism; Molecular Biology; model Organisms

DOI:  https://doi.org/10.1016/j.xpro.2025.104024
Medicina (B Aires). 2025 ;85(4): 810-821

[Normal and emergency hematopoiesis: current concepts and clinical implications].

Olivia Gelo, María Cecilia Foncuberta, Julio César Sánchez Ávalos.

Recent advancements in techniques applied to the study of bone marrow histoarchitecture and the identification of genetic, epigenetic, proteomic, and metabolic characteristics of hematopoietic progenitor cells have facilitated a more comprehensive understanding of the interaction between these cells and the marrow microenvironment, as well as the mechanism of hematopoiesis. Hematopoiesis is maintained by primitive progenitor cells or stem cells, which undergo asymmetric division, enabling self-renewal. Pluripotent progenitor cells, which also possess self-renewal capabilities, are responsible for sustaining hematopoiesis. Hematopoietic progenitor cells represent a population in continuous and progressive differentiation towards mature cells, exhibiting plasticity to modify their proliferation and differentiation in response to received signals. In acute or chronic infections or inflammation, inflammatory cytokines and/or extracellular vesicles induce genetic, epigenetic, proteomic, and metabolic changes in hematopoietic progenitor cells, initiating emergency hematopoiesis. Emergency hematopoiesis constitutes an alteration of hematopoiesis characterized by: 1) increased myelopoiesis, with decreased lymphopoiesis and erythropoiesis, 2) increased release of hematopoietic progenitor cells into peripheral blood and development of extramedullary hemopoiesis, 3) generation of two cellular subpopulations of the innate immune system with defined characteristics and functions: a) innate immune memory cells (trained immunity), and b) myeloid suppressor cells. These changes can induce alterations in the neutrophil/lymphocyte and monocyte/lymphocyte ratio in the blood count, the increase of which has adverse prognostic value in various chronic inflammatory diseases and especially in neoplasms.

Keywords: emergency hematopoiesis; inflammation and neoplasms; innate immune memory; myeloid suppressor cells; trained immunity
Inflamm Bowel Dis. 2025 Aug 12. pii: izaf150. [Epub ahead of print]

Ulcerative Colitis Aggravates Periodontitis via Inducing Myelopoiesis.

Xinyi Kuang, Xiaoyue Jia, Xian Peng, Xin Zheng, Lei Zhao, Jing Xie, Liwei Zheng, Xin Xu.

   OBJECTIVES: The intercorrelations between periodontitis and inflammatory bowel disease have been recognized for years. Accumulating evidence has shown that patients with ulcerative colitis (UC) have a higher prevalence and severity of periodontitis. However, the underlying mechanisms by which UC aggravates periodontal destruction are still unclear.
METHODS: Multiple murine models, including DSS-induced colitis (DIC)/ligature-induced periodontitis (LIP), DIC/LIP rescued by berberine, and LIP after DIC remission models were established to investigate the mechanisms by which UC exacerbates periodontal inflammation.
RESULTS: DIC mice exhibited a disrupted intestinal barrier with dysbiotic gut microbiota, corroborating the elevated serum levels of LPS and IL-1. Compared to DIC-free/LIP mice, DIC/LIP mice showed aggravated alveolar bone resorption, with enrichment of neutrophil extracellular traps (NETs) in periodontal tissues. DIC promoted myelopoiesis of hematopoietic stem and progenitor cells (HSPCs) by up-regulating the myeloid differentiation pathway. Intragastric administration of berberine dampened DIC and rescued the myeloid skewing of HSPCs, consequently alleviating periodontal destruction. Intriguingly, LIP induction after DIC remission still exhibited aggravated periodontal destruction and myeloid skewing of HSPCs, indicating a UC-trained immunity against periodontal damage.
CONCLUSIONS: Increased gut permeability and microbial dysbiosis in UC elevate the serum level of LPS and IL-1, inducing myeloid skewing of HSPCs with an immune memory. Generation of inflammatory potential myeloid cells causes NETs accumulation and aggravates periodontal destruction in the UC-related periodontitis.

Keywords:  HSPCs; neutrophils extracellular traps; periodontitis; trained immunity; ulcerative colitis

DOI:  https://doi.org/10.1093/ibd/izaf150
Phytother Res. 2025 Aug 12.

Coptisine Improves Liver Inflammation in Sepsis by Regulating STAT1/IRF1/GPX4 Signaling-Mediated Kupffer Cells Ferroptosis.

Bingwen Zhu, Chang Sun, Dongrong Luo, Yuying Liang, Aolin Jiang, Zehui Jiang, Haihua Luo, Gang Yuan, Chenyang Huang, Shaoqing Liu, Lei Li, Yong Jiang.

  Sepsis is a life-threatening condition characterized by organ dysfunction, with the liver being particularly vulnerable due to inflammation triggered by Kupffer cell activation. Ferroptosis, an iron-dependent form of regulated cell death associated with macrophages, has emerged as a key pathogenic mechanism. This study aimed to investigate the protective effects of coptisine (COP), a natural alkaloid, against sepsis-induced hepatic ferroptosis and injury using in vivo and in vitro models. Sepsis was induced in mice via cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) challenge, followed by treatment with COP, ferrostatin-1 (Fer-1, a ferroptosis inhibitor), or 2-NP. In vitro, Kupffer cells were stimulated with LPS + IFN-γ and erastin to induce inflammation and ferroptosis, then treated with COP or Fer-1. Multiple techniques were employed, including histopathology, enzyme-linked immunosorbent assay (ELISA), quantitative PCR (qPCR), Western Blot, immunofluorescence (IF), molecular docking, bio-layer interferometry (BLI), and cellular thermal shift assay (CETSA), to evaluate the STAT1/IRF1/GPX4 signaling axis. Additionally, serum markers from sepsis patients were analyzed. In septic mice, COP significantly attenuated liver injury, inflammation, and ferroptosis. In Kupffer cells, COP suppressed erastin-induced ferroptosis. Mechanistically, COP directly bound to STAT1, inhibiting its phosphorylation and subsequent IRF1 activation, while restoring GPX4 expression. Overexpression of STAT1 abolished the protective effects of COP. Clinical data revealed elevated p-STAT1 and IRF1 levels alongside reduced GPX4 in sepsis patients. COP exerts hepatoprotective effects in sepsis by inhibiting ferroptosis through the STAT1/IRF1/GPX4 pathway, highlighting its potential as a therapeutic agent for sepsis-associated liver injury.

Keywords:  Kupffer cells; STAT1; coptisine; ferroptosis; liver inflammation; patients; sepsis

DOI:  https://doi.org/10.1002/ptr.70063
Stem Cell Res Ther. 2025 Aug 10. 16(1): 440

Trained human bone marrow mesenchymal stem cells restore tissue immuno-microenvironment in fulminant hepatic failure mice.

Bingqi Li, Xiaofei Zeng, Jing Jiang, Qian Zhou, Li Tong, Xi Liang, Jiaojiao Xin, Xi Chen, Xiao Wu, Yuheng Kong, Shiwen Ma, Jinjin Luo, Wei Qiang, Bing Zhu, Xinhua Luo, Jun Li, Dongyan Shi.

   BACKGROUND: Trained immunity with human bone marrow mesenchymal stem cells (hBMSC) is a promising approach to liver regeneration. This study aimed to clarify the trained-hBMSC (T-hBMSC) in restoring tissue immuno-microenvironment in fulminant hepatic failure (FHF) mice.
METHODS: hBMSC trained with tumor necrosis factor-α and interferon-γ were phenotypically characterized in vitro. FHF mouse models were established in male Balb/c mice via tail vein injection of concanavalin A. The therapeutic potential of T-hBMSC was evaluated through transplantation into FHF mice. Transcriptomic analysis was performed to elucidate the mechanism of liver regeneration post-transplantation of T-hBMSC.
RESULTS: T-hBMSC with the characteristics of trilineage differentiation potential showed that pro-inflammatory (IL1β, IL8, both p < 0.0001) and immunoregulatory genes (PDL1, IDO1, both p < 0.0001) were significantly upregulated compared to untrained-hBMSC (UT-hBMSC). Time-trajectory analysis revealed downregulation of pro-inflammatory genes (IL6, IL8, and IL1α) and upregulation of immunomodulatory genes (IDO1) in T-hBMSC upon mimic-stimulation, characterized by distinct transcriptional programs. The liver function (ALT, AST) and inflammatory cytokines (IL6, MCP1, both p < 0.01) levels were significantly improved in the T-hBMSC-treated mice. The survival status of the T-hBMSC group was superior to the UT-hBMSC group, although there was no statistical significance. Histological analysis confirmed reduced necrosis and fewer infiltrating CD45+ immune cells in the T-hBMSC-treated mice. Significant downregulation of immune response (TNF & IL-17 signaling pathways and neutrophil chemotaxis) and upregulation of metabolic pathways were observed in the T-hBMSC group, associated with enhanced liver regeneration. The proportion of anti-inflammatory F4/80+CD163+ macrophages was increased in the liver of T-hBMSC group.
CONCLUSION: T-hBMSC exhibited enhanced immunomodulation, effectively rescuing liver failure and reducing inflammation via restoring the immune-microenvironment. These findings highlighted the potential of trained immunity as a novel strategy for the treatment of liver failure.

Keywords:  Bone marrow mesenchymal stem cells; Fulminant hepatic failure; Immune microenvironment; Trained immunity

DOI:  https://doi.org/10.1186/s13287-025-04540-x
Nat Commun. 2025 Aug 14. 16(1): 7551

Astrocyte priming enhances microglial Aβ clearance and is compromised by APOE4.

Se-In Lee, Jichang Yu, Hyein Lee, Buyun Kim, Min Jun Jang, Hyeonbin Jo, Na Yeon Kim, Malk Eun Pak, Jae Kwang Kim, Sukhee Cho, Hong-Hee Won, Min Soo Kim, Fan Gao, Younghoon Go, Jinsoo Seo.

The innate immune system can develop a form of memory called priming, where prior exposure to a stimulus enhances subsequent responses. While well-characterized in peripheral immunity, its function in brain-resident cells such as astrocytes under non-disease conditions remains unclear. Here we show that human astrocytes derived from the induced pluripotent stem cells of healthy female donors, but not microglia, acquire a primed state following transient immune stimulations. Upon subsequent exposure to amyloid-β (Aβ), these astrocytes secrete elevated levels of cytokines and promote microglial Aβ uptake. In contrast, astrocytes carrying the Alzheimer's disease (AD) risk allele APOE4 exhibit reduced priming and fail to support microglial phagocytosis. These findings are validated in astrocyte-microglial co-cultures, cerebral organoids, and male mice, where astrocyte priming enhances Aβ clearance in an APOE4-sensitive manner. Our findings identify astrocytic immune memory as a modulator of microglial function and Aβ pathology, providing insights into how early protective responses in AD may be disrupted by genetic risk factors.

DOI: https://doi.org/10.1038/s41467-025-62995-1
PLoS Biol. 2025 Aug;23(8): e3003311

The ghost of infections past: Accounting for heterogeneity in individual infection history improves accuracy in epidemic forecasting.

Pedro F Vale, Chadi M Saad-Roy, Mike Boots.

Variation in infection history is an important but often underappreciated driver of individual variability in responses to infections. Such individual heterogeneity in immune responses, stemming from variable previous exposure to pathogens, subsequently influences epidemiological outcomes. By comparing research on innate immune priming in invertebrates, which lack adaptive immune memory but demonstrate enhanced responses to re-infections, to patterns seen in vertebrates, this Essay reveals broad implications for disease dynamics. Insights from mathematical modelling and experimental data highlight the critical need to integrate evolutionary disease ecology into public health initiatives to better predict and manage infectious diseases.

DOI: https://doi.org/10.1371/journal.pbio.3003311
Cell Syst. 2025 Jul 31. pii: S2405-4712(25)00179-6. [Epub ahead of print] 101346

Integrated time-series analysis and high-content CRISPR screening delineate the dynamics of macrophage immune regulation.

Peter Traxler, Stephan Reichl, Lukas Folkman, Lisa Shaw, Victoria Fife, Amelie Nemc, Djurdja Pasajlic, Anna Kusienicka, Daniele Barreca, Nikolaus Fortelny, André F Rendeiro, Florian Halbritter, Wolfgang Weninger, Thomas Decker, Matthias Farlik, Christoph Bock.

  Macrophages are innate immune cells involved in host defense. Dissecting the regulatory landscape that enables their swift and specific response to pathogens, we performed time-series analysis of gene expression and chromatin accessibility in murine macrophages exposed to various immune stimuli, and we functionally evaluated gene knockouts at scale using a combined CROP-seq and CITE-seq assay. We identified new roles of transcription regulators such as Spi1/PU.1 and JAK-STAT pathway members in immune cell homeostasis and response to pathogens. Macrophage activity was modulated by splicing proteins SFPQ and SF3B1, histone acetyltransferase EP300, cohesin subunit SMC1A, and mediator complex proteins MED8 and MED14. We further observed crosstalk among immune signaling pathways and identified molecular drivers of pathogen-induced dynamics. In summary, this study establishes a time-resolved regulatory map of pathogen response in macrophages, and it describes a broadly applicable method for dissecting immune-regulatory programs through integrative time-series analysis and high-content CRISPR screening. A record of this paper's transparent peer review process is included in the supplemental information.

Keywords:  CROP-seq; bioinformatics; innate immunity; machine learning; macrophages; multi-omics profiling; pathogen infection; single-cell CRISPR sequencing; systems immunology; time-series analysis

DOI:  https://doi.org/10.1016/j.cels.2025.101346
Nat Commun. 2025 Aug 12. 16(1): 7435

A citrullinated histone H3 monoclonal antibody for immune modulation in sepsis.

Wenlu Ouyang, Yuchen Chen, Tao Tan, Yujing Song, Tao Dong, Xin Yu, Kyung Eun Lee, Xinyu Zhou, Zoe Tetz, Sophia Go, Xindi Zeng, Liujiazi Shao, Chao Quan, Ting Zhao, Yuzi Tian, Katsuo Kurabayashi, Hua Jin, Jichun Ma, Jingdong Qin, Brandon Williams, Qingtian Li, Gui-Dong Zhu, Hasan B Alam, Kathleen A Stringer, Yongqing Li, Jianjie Ma.

Citrullinated histone H3 (CitH3), released from immune cells during early sepsis, drives a vicious cycle of inflammation through excessive NETosis and pyroptosis, causing immune dysfunction and tissue damage. To regulate this process, we develop a humanized CitH3 monoclonal antibody (hCitH3-mAb) with high affinity and specificity to target this process. In murine models, hCitH3-mAb reduces cytokine production, mortality and acute lung injury (ALI) caused by LPS and Pseudomonas aeruginosa while enhancing bacteria phagocytosis in the lungs, spleen, and liver. Using pre-equilibrium digital ELISA (PEdELISA), we identify an optimal therapeutic window for hCitH3-mAb in sepsis-induced ALI. In parallel, we explore the molecular mechanism underlying CitH3-driven inflammation. We find that in macrophages, CitH3 activates Toll-like receptor 2 (TLR2), triggering Ca2+-dependent PAD2 auto-citrullination and nuclear translocation, amplifying CitH3 production via a harmful feedback loop. The hCitH3-mAb treatment effectively disrupts this cycle and restores macrophage function under septic conditions. Together, these findings highlight both the therapeutic potential of hCitH3-mAb and provide a deep mechanistic insight into the CitH3-PAD2 axis in sepsis, supporting its further development for treating immune-mediated diseases.

DOI: https://doi.org/10.1038/s41467-025-62788-6
Adv Sci (Weinh). 2025 Aug 11. e17493

Tumor Extracellular Vesicles Aggravate Mitochondrial Damage in Myocardial Ischemia/Reperfusion Injury.

Zhongting Mei, Qian Liu, Guoxin Liu, Manjie Zhang, Jiaxin Fang, Xuting He, Xueqi He, Zhengwei Qin, Ronghua Liu, Chuang Liu, Hongyu Ji, Yuechao Dong, Ye Yuan, Baofeng Yang, Weijie Du.

  Cancer patients have a higher risk of all types of cardiovascular diseases (CVDs). Cardiologists are encountering a growing number of cancer patients with CVDs, and an increasing number of cancer patients undergoing percutaneous coronary intervention (PCI). The mechanistic link between cancer and CVDs remains elusive. Here, the meta-analysis shows the increased incidence ratio of all-cause mortality and cardiovascular (CV) mortality in patients undergoing PCI with cancer compared with non-cancer. We experimentally demonstrated that cancer aggravated mitochondrial dysfunction and myocardial ischemia/reperfusion (I/R) injury in two models of lung cancer in mice. Plasma extracellular vesicles (EVs) derived from cancer mice exacerbated cardiac I/R injury in vivo and in vitro, while inhibition of tumor EVs secretion by lipid-coated polyacrylic acid/calcium phosphate nanoparticles delivered a neutral sphingomyelinase inhibitor (GW4869) showed the opposite results. Lung-specific miR-485-3p sponges mediated by Adeno-associated virus 6 suppress cardiac damage and mitochondrial dysfunction in CC10-KRASG12D mice post-I/R. Mechanistically, PPARGC1A/PGC-1α is post-transcriptionally repressed by miR-485-3p in cardiomyocytes, leading to the inhibition of mitochondrial complex I subunits and ATP synthesis. Taken together, our findings reveal for the first time that cancer can aggravate cardiac injury and mitochondrial dysfunction by releasing miR-485-3p-enriched extracellular vesicles derived from cancer cells.

Keywords:  PPARGC1A/PGC‐1α; cancer; extracellular vesicles; miR‐485‐3p; mitochondrial dysfunction; myocardial ischaemia/reperfusion; percutaneous coronary intervention

DOI:  https://doi.org/10.1002/advs.202417493
J Immunol. 2025 Aug 07. pii: vkaf164. [Epub ahead of print]

Individual subsets of alternatively-activated macrophages differentially contribute to tissue repair and the resolution of inflammation.

Katharina Weishaupt, Jochen Ackermann, Philipp Burger, David Chambers, Karolina Grimm, Rita Weinkam, Alexandra Correa Zamora, Jean-Philippe Auger, Benjamin Frey, Georg Schett, Gerhard Krönke.

  Although alternatively-activated macrophages (AAM) have been implicated in the resolution of inflammation and tissue repair, their exact role, heterogeneity and origin in vivo remain incompletely defined. Here we show that distinct subsets of macrophages can acquire alternatively activated phenotypes in response to tissue injury where these cellular subsets display contrasting spatiotemporal dynamics and differentially contribute to the resolution of inflammation and tissue repair. By studying a model of cardiotoxin-induced muscle injury, we identify a population of monocyte-derived AAM characterized by expression of arginase-1 (Arg-1) and triggering receptor expressed on myeloid cells 2 (Trem2) that emerged in response to injury and fostered clearance of dying neutrophils and necrotic myofibers as well as the subsequent resolution of inflammation. A second population of AAM, which were marked by robust expression of resistin-like molecule alpha (Relmα) and mannose receptor C-type 1 (CD206), displayed a predominantly resident character and clustered around capillaries where they coordinated the recruitment of eosinophils as well as the subsequent process of tissue repair. Our data thus indicate a substantial heterogeneity among AAM subsets and help to define their specialized functions and roles during inflammation and tissue repair.

Keywords:  cardiotoxin-induced muscle injury; macrophage polarization; resolution of inflammation; tissue damage

DOI:  https://doi.org/10.1093/jimmun/vkaf164
Immunity. 2025 Aug 09. pii: S1074-7613(25)00326-7. [Epub ahead of print]

Succinate preserves CD8+ T cell fitness to augment antitumor immunity.

Kaili Ma, Hongcheng Cheng, Lin Wang, Han Xiao, Fenghua Liu, Yu Yang, Zhen Xiao, Kun Tang, Shicheng Li, Gang Wang, Minmin Ge, Jiajia Wang, Xiaowei Liu, Hai-Xi Sun, Ziyi Luo, Zhimin Gu, Ping-Chih Ho, Guideng Li, Lianjun Zhang.

  Succinate, a tricarboxylic acid cycle intermediate, accumulates in tumors with succinate dehydrogenase (SDH) mutations. Although succinate is recognized for modulating CD8+ T cell cytotoxicity, its impact on T cell differentiation remains poorly understood. Here, we reveal that succinate accumulation in tumors lacking the SDH subunit B (SDHB) enhanced tumor-reactive CD8+ T cell-mediated immune responses. Sustained succinate exposure promoted CD8+ T cell survival and facilitated the generation and maintenance of stem-like subpopulations. Mechanistically, succinate enhanced mitochondrial fitness through Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-mediated mitophagy and also promoted stemness-associated gene expression via epigenetic modulation. Succinate-conditioned CD8+ T cells displayed superior long-term persistence and tumor control capacity. Moreover, succinate enrichment signature correlates with favorable clinical outcomes in certain melanoma and gastric cancer patients receiving immune checkpoint blockade therapy. These findings reveal how succinate preserves T cell stemness and highlight the therapeutic potential of succinate supplementation for enhancing T cell immunotherapy efficacy.

Keywords:  SDHB-deficient tumor; T cell stemness; TCF-1; antitumor immune response; epigenetic reprogramming; exhaustion; immune checkpoint blockade; mitochondrial fitness; mitophagy; succinate

DOI:  https://doi.org/10.1016/j.immuni.2025.07.017
Adv Healthc Mater. 2025 Aug 15. e01426

Biologically Active Implants Prevent Mortality in a Mouse Sepsis Model.

Martin Stark, Fereshteh Bayat, Sara Rahmani, Mathura Thirugnanasampanthar, Taylor Kramer, Elise Schwarz, David Wilson, Jeffrey I Weitz, Zeinab Hosseinidoust, Tohid F Didar.

  Implant-associated infections remain a significant complication in medicine. often leading to chronic infection, tissue damage, or implant failure. To address this, this work develops a modular, triple-action titanium implant that integrates bacterial repellency, bactericidal activity, and enhanced tissue integration. The implant comprises medical-grade titanium with a co-deposited layer of bacteriophages and collagen stably embedded within a repellent lubricant layer. The collagen layer promotes cell deposition and spreading in vitro. When tested against Pseudomonas aeruginosa, the coating reduces bacterial load by 3.2 logs on the surface and 1.9 logs in the medium, outperforming conventional liquid-infused surfaces. A modified version targeting Staphylococcus aureus achieves 4.1-log and 5.2-log reductions, respectively, after a 6-h incubation. When challenging the coating in a sepsis survival model of Pseudomonas aeruginosa infection, mice with the phage-activated implants exhibit a 100% survival rate and fully recover from the infection. In comparison, those with pathogen-repellent and untreated titanium implants show survival rates of only 30% and 10%, respectively. Furthermore, phage, but no bacteria, are detected in the bloodstream of mice implanted with phage-activated titanium, suggesting that locally implanted phage-biomaterials can distribute systemically to control blood infections. Therefore, the engineered phage-activated, triple-action biomaterials may prevent implant-associated infections locally and systemically.

Keywords:  antibacterial‐coating; bacteriophages; medical implant; mouse sepsis model

DOI:  https://doi.org/10.1002/adhm.202501426