bims-traimu 2025-11-02 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–11–02
twelve papers selected by
Yantong Wan, Southern Medical University

Pleiotropic Mucosal Innate Immune Memory in the Gastrointestinal Tract.
Reversing inflammatory diseases via trained immunity: mechanisms, challenges, and prospects.
Induction of myelopoiesis by Candida dubliniensis drives protective trained immunity against sepsis in a Card9-dependent manner.
Post-pandemic upsurge of group A streptococcus infections: potential link to impaired herd trained immunity following COVID-19 lockdowns.
Trained immunity in atherosclerosis: plasticity, metabolic-vascular axis, and AI-driven precision remodeling.
Exploring trained immunity to complement vaccination against Streptococcus suis in swine.
Nano-strategy empowering trained immunity in vaccines.
Circulating FABP5 released by dying macrophages function as a DAMP to exacerbate septic inflammation.
Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity.
Acute hypoxia drives long-term dysfunctional neutrophil immunity.
The role of an anti-inflammatory molecule AIM/CD5L in gut ischemia/reperfusion injury of male mice.
Immunomodulatory Nanozymes Eradicate Intracellular Infections and Rescue Immunoparalysis for Treating Multidrug-Resistant Bacterial Sepsis.

Int J Mol Sci. 2025 Oct 16. pii: 10093. [Epub ahead of print]26(20):

Pleiotropic Mucosal Innate Immune Memory in the Gastrointestinal Tract.

Rachel H Cohen, Sean P Colgan, Ian M Cartwright.

  Research in the past fifteen years has established that innate immune cells can develop immune memory, termed trained immunity. Trained innate immune cells exhibit distinct lasting epigenetic and metabolic changes that prime these cells upon repeated exposure. The gastrointestinal tract provides an important immunological barrier and is home to many innate immune cells, where trained immunity serves an essential role. This review summarizes what is currently known about the basic mechanisms behind innate immune memory, the roles of innate immune cells within the intestine, intestinal-specific trained immunity, and therapeutic potential for targeting trained immunity in the context of gastrointestinal disorders.

Keywords:  inflammatory bowel disease; innate immune memory; mucosal inflammation

DOI:  https://doi.org/10.3390/ijms262010093
Front Immunol. 2025 ;16 1666233

Reversing inflammatory diseases via trained immunity: mechanisms, challenges, and prospects.

Wanli Xu, Zhilin Guo, Tingyun Xu, Junjie Chen, Leyi Chen, Wenan Xu.

  Chronic inflammatory diseases are widespread and often accompanied by comorbidities, making treatment challenging. Current immunosuppressive and anti-inflammatory therapies have limited efficacy and significant side effects, and are insufficient to address the complexity of coexisting conditions. This review explores recent advances in innate immune memory, also known as trained immunity, and its potential role in inflammatory diseases. We hypothesize that targeting the regulatory mechanisms of trained immunity may lead to novel therapeutic strategies that more effectively control inflammation and improve disease outcomes. Finally, we highlight that the interplay between trained immunity and inflammatory diseases remains incompletely understood, and further research is needed to elucidate its mechanisms and clinical translational potential.

Keywords:  epigenetic reprogramming; immune system; inflammation; inflammatory diseases; innate immune memory; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1666233
mBio. 2025 Oct 31. e0290625

Induction of myelopoiesis by Candida dubliniensis drives protective trained immunity against sepsis in a Card9-dependent manner.

Shannon Esher Righi, Elizabeth A Lilly, Amanda J Harriett, Patrick W Daly, MaryJane Jones, Chad Steele, Mairi C Noverr, Paul L Fidel.

  Trained immunity is a long-term functional reprogramming of innate cells that allows for the formation of immune memory akin to adaptive responses, but with a more rapid nonspecific response. We recently identified an anti-inflammatory trained immunity response, termed trained tolerogenic immunity (TTI), induced by low virulence Candida dubliniensis, that protects against acute lethal polymicrobial sepsis via myeloid-derived suppressor cells (MDSCs). Trained immunity and MDSCs arise following hematopoietic stem and progenitor cell (HSPC) expansion in the bone marrow. Here, we show that C. dubliniensis induces inoculum-dependent protection and HSPC expansion, whereas depletion of HSPCs following C. dubliniensis immunization abrogates protection. We further show that myeloid progenitors and putative MDSCs are increased in the bone marrow following C. dubliniensis immunization, and that HSPC depletion results in reduced MDSC influx into the peritoneal cavity following lethal challenge. Bone marrow cytokine analysis revealed that mediators associated with MDSC development and trafficking, including G-CSF, CXCL2, and CCL2, are upregulated following C. dubliniensis immunization. Finally, we find that the C-type lectin receptor adaptor protein Card9 is required for C. dubliniensis-induced protection and HSPC expansion, but not fungal trafficking to the bone marrow. Taken together, these results suggest that Card9-dependent fungal recognition in the bone marrow drives myelopoiesis and the induction of immunosuppressive MDSCs that are protective against lethal inflammation and sepsis.IMPORTANCECells of the innate immune system can be "trained" by inducers to have enhanced memory responses, a phenomenon known as trained immunity. We recently identified an anti-inflammatory training response that is induced by low virulence fungal species (i.e., Candida dubliniensis) and is protective against acute lethal polymicrobial sepsis. Trained immunity inducers, including C. dubliniensis, can access the bone marrow and direct hematopoietic responses. Here, we demonstrate that protection is correlated with C. dubliniensis-induced bone marrow expansion, which directs a myeloid bias in the bone marrow and ultimately results in the expansion of protective myeloid-derived suppressor cells. Involvement of the C-type lectin receptor adaptor protein Card9 in the protective response suggests fungal recognition in the bone marrow drives this response. These findings offer new insights into how trained immunity inducers direct differential outcomes, which will inform the development of novel immunotherapeutics to exploit the full spectrum of trained immune responses.

Keywords:  Candida; MDSC; myelopoiesis; sepsis; trained immunity

DOI:  https://doi.org/10.1128/mbio.02906-25
Front Immunol. 2025 ;16 1684332

Post-pandemic upsurge of group A streptococcus infections: potential link to impaired herd trained immunity following COVID-19 lockdowns.

Janusz Marcinkiewicz.



Keywords:  group A streptococcus; herd trained immunity; innate memory; pandemic lockdown; resurge of infections

DOI:  https://doi.org/10.3389/fimmu.2025.1684332
Front Immunol. 2025 ;16 1669796

Trained immunity in atherosclerosis: plasticity, metabolic-vascular axis, and AI-driven precision remodeling.

Bing Zhao, Jiayang Wan, Huifen Zhou, Jiehong Yang, Haitong Wan.

  Chronic inflammation linked to atherosclerosis is closely related to a trained immunoregulatory network. Traditional studies primarily focus on the pro-inflammatory memory of monocytes, they frequently neglect important aspects such as the cell's plasticity, interactions between different organs, and the dynamic regulation of the metabolism-vascular axis. This review presents four novel frameworks, including the trained immunity plasticity spectrum model. It demonstrates how monocytes maintain a dynamic balance between pro-inflammatory, tolerogenic, and anti-inflammatory phenotypes, regulated by mTOR/AMPK signaling and competitive histone modifications. The trained immunity-metabolism-vascular axis shows that metabolic disorders can change the way immune memory is formed. They achieve this by modifying the vascular microenvironment through epigenetic changes, exosomes, and products of mitochondrial stress. The cross-organ trained immunity framework reveals how remote epigenetic communication between the bone marrow, gut, and liver influences the development of monocytes. Finally, dynamic immune reprogramming integrates CRISPR-based epigenetic editing, metabolism-focused interventions, and AI-driven multi-omics predictions. This approach signifies a major transition from simply alleviating symptoms to accurately reshaping immune memory. This review reinterprets the immunometabolic mechanisms of atherosclerosis. It also lays the foundation for personalized therapies enhanced by AI and explores new interdisciplinary research avenues.

Keywords:  AI-driven precision medicine; atherosclerosis; immune plasticity; metabolic-vascular axis; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1669796
Dev Comp Immunol. 2025 Oct 24. pii: S0145-305X(25)00187-9. [Epub ahead of print]172 105498

Exploring trained immunity to complement vaccination against Streptococcus suis in swine.

Lidia Sánchez-Morales, Marta Pérez-Sancho, Teresa García-Seco, Ana Balseiro, Andrea Pérez-Domingo, Aránzazu Buendía, Alberto Diez-Guerrier, María García de Garnica García, Patricia Mareque, María de Los Ángeles Risalde, Christian Gortázar, Mercedes Domínguez, Lucas Domínguez.

  Streptococcus suis is a major pathogen in swine, causing septicaemia, meningitis, and arthritis. Effective control is complicated by the presence of multiple serotypes, genetic heterogeneity, and interference of maternal antibodies with vaccine efficacy. Moreover, the emergence of antibiotic-resistant strains poses additional challenges. Trained immunity, a process of innate immune memory induced by certain stimuli, has been proposed as a novel approach to enhance host defense mechanisms. This study aimed to evaluate whether a mycobacterial-derived immunomodulator (dpB) administered with a specific S. suis vaccine could improve protection in pigs. Thirty-two weaned pigs were allocated into four groups: vaccine alone, vaccine and live dpB, vaccine and inactivated dpB, and non-immunized controls. After two immunizations, animals were challenged with a S. suis serotype 2 strain. Immune responses were assessed through ex vivo blood stimulation, cytokine measurement and phagocytosis assays. The group receiving vaccine and inactivated dpB presented a better response, including reduced bacterial loads in tissues, less severe lung lesions and elevated pre-challenge cytokine levels. Clinically, these animals showed milder symptoms and lower bacterial dissemination post-challenge. While trained immunity remains a relatively new concept in veterinary immunology, these results suggest that inactivated dpB, when combined with specific vaccination, could serve as an effective complementary strategy to improve protection against S. suis. Further research is needed to elucidate the underlying mechanisms and to establish its potential role in comprehensive disease prevention programs.

Keywords:  Epigenetic reprogramming; Immunomodulation; Innate memory; Mycobacteria; Streptococcosis

DOI:  https://doi.org/10.1016/j.dci.2025.105498
J Control Release. 2025 Oct 27. pii: S0168-3659(25)00973-3. [Epub ahead of print] 114359

Nano-strategy empowering trained immunity in vaccines.

Litong Wang, Yitao Zhang, Shenyu Wang, Xin Shen, Junlei Zhang, Jian You, Lihua Luo.

  Vaccines represent a significant milestone in the history of human medical development and have played an indispensable role in safeguarding public health. The incorporation of nanotechnology holds promise for mitigating the adverse effects of conventional vaccines while concurrently enhancing their immunogenicity. Immune memory is a critical factor in assessing the efficacy and longevity of vaccines. Traditionally, immune memory has been perceived as a function exclusive to the adaptive immune system. However, recent studies have demonstrated that immune memory can also be established within the innate immune system, a phenomenon referred to as trained immunity. This article reviews nanovaccines associated with trained immunity, specifically analyzing the primary nano-strategies that empower trained immunity in vaccines. Such strategies are expected to inform the design of future vaccines that comprehensively induce immune functions. For example, optimizing the physical properties of nanocarriers can significantly improve the transport and utilization of nanoparticles by innate immune cells, while specific antigen release systems can enhance the precision of drug release regarding both location and timing, thereby prolonging the duration of trained immunity. This is anticipated to provide valuable insights for future vaccine designs aimed at inducing comprehensive immune responses.

Keywords:  Adjuvant; Nano-strategy; Trained immunity; Vaccine

DOI:  https://doi.org/10.1016/j.jconrel.2025.114359
Cell Rep. 2025 Oct 30. pii: S2211-1247(25)01268-9. [Epub ahead of print]44(11): 116497

Circulating FABP5 released by dying macrophages function as a DAMP to exacerbate septic inflammation.

Rong Wu, Yunong Zeng, Jiaochan Han, Lei Li, Qing-Ming Xiong, Shuyu Li, Shanshan Fu, Ping Qin, Ze Wang, Yi He, Zhengzheng Yan, Weidong Xiao, Zhenhua Zeng, Zhe-Xiong Lian, Zhi-Bin Zhao, Wei Xiao, Yong Jiang, Shenhai Gong.

  Damage-associated molecular patterns (DAMPs) often cause an exaggerated immune response. Fatty acid-binding protein 5 (FABP5) is traditionally considered a cytosolic protein responsible for the transport of fatty acids. However, little is known about the role of FABP5 in sepsis. Herein, we found that circulating FABP5 levels were higher in patients with sepsis and were associated with adverse outcomes. The circulating FABP5 originated mainly from macrophage pyroptosis in the later stages of sepsis despite a decrease in cytoplasm-resident FABP5 expression. Functionally, circulating FABP5 penetrated the living macrophage membrane and bound to the intracellular domain of TLR4, ultimately inducing secondary inflammation through the NF-κB and MAPK pathways. Unlike circulating oxidized FABP5, cytoplasm-resident FABP5 was present in its reduced form and suppressed macrophage pyroptosis. Clearance of circulating DAMP FABP5 by preventing the passive release from dying macrophages or using a specific blocking antibody can improve survival in mice with sepsis.

Keywords:  CP: immunology; DAMP; FABP5; secondary inflammation; sepsis

DOI:  https://doi.org/10.1016/j.celrep.2025.116497
Nat Immunol. 2025 Nov;26(11): 1903-1915

Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity.

PHOSP-COVID Study Collaborative Group

The long-term impact of systemic hypoxia resulting from acute respiratory distress syndrome (ARDS) on the function of short-lived innate immune cells is unclear. We show that patients 3-6 months after recovering from ARDS have persistently impaired circulating neutrophil effector functions and an increased susceptibility to secondary infections. These defects are linked to a widespread loss of the activating histone mark H3K4me3 in genes that are crucial for neutrophil activities. By studying healthy volunteers exposed to altitude-induced hypoxemia, we demonstrate that oxygen deprivation alone causes this long-term neutrophil reprogramming. Mechanistically, mouse models of systemic hypoxia reveal that persistent loss of H3K4me3 originates in proNeu and preNeu progenitors within the bone marrow and is linked to N-terminal histone 3 clipping, which removes the lysine residue for methylation. Thus, we present new evidence that systemic hypoxia initiates a sustained maladaptive reprogramming of neutrophil immunity by triggering histone 3 clipping and H3K4me3 loss in neutrophil progenitors.

DOI: https://doi.org/10.1038/s41590-025-02301-9
Nat Immunol. 2025 Nov;26(11): 1861-1862

Acute hypoxia drives long-term dysfunctional neutrophil immunity.

DOI: https://doi.org/10.1038/s41590-025-02335-z
Mol Med. 2025 Oct 29. 31(1): 321

The role of an anti-inflammatory molecule AIM/CD5L in gut ischemia/reperfusion injury of male mice.

Russell Hollis, Gaifeng Ma, Alok Jha, Megan Tenet, Takayuki Kato, Monowar Aziz, Ping Wang.

   INTRODUCTION: Resolution of acute gut ischemia causes reperfusion injury, resulting in the release of damage-associated molecular patterns (DAMPs) and tissue injury. A key DAMP, extracellular cold-inducible RNA-binding protein (eCIRP), exacerbates inflammation in reperfusion injury, contributing to organ failure and death. Apoptosis inhibitor of macrophage (AIM or CD5L) is a glycoprotein secreted by macrophages which can influence the activity of immune cells. We seek to investigate AIM expression in ischemia/reperfusion (I/R) and elucidate its anti-inflammatory role in macrophages and intestinal epithelial cells.
METHODS: Male mice underwent occlusion of the superior mesenteric artery for 60 min, followed by reperfusion for 4 h before sample collection. AIM expression in blood and tissue was evaluated by qPCR, Western blot, and ELISA. Primary peritoneal macrophages from male mice, IEC-6 intestinal epithelial cells, and RAW 264.7 macrophages were stimulated with recombinant mouse (rm) CIRP (denoted eCIRP) and treated with rmAIM. Cytokine levels were assessed by ELISA and qPCR. Metabolic function was measured in macrophages using the Agilent Seahorse XF Pro analyzer. Interactions involving AIM, eCIRP, and eCIRP's receptors, Toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells-1 (TREM-1), were elucidated by in silico approaches.
RESULTS: Pulmonary AIM mRNA expression decreased by 55.9% (p = 0.018), and protein levels decreased by 26.9% (p = 0.032) in gut I/R mice compared to sham mice. Plasma AIM concentration decreased by 22.0% (p = 0.0362) in gut I/R mice compared to sham. eCIRP treatment increased pro-inflammatory cytokine production by macrophages and intestinal epithelial cells. This increase was significantly attenuated by co-treatment with rmAIM. Macrophages also increased basal oxygen consumption rate by 66.7% and ATP production by 70.3% when treated with rmAIM compared to eCIRP stimulation alone (p < 0.0001). Computational modeling predicted strong interactions between AIM and eCIRP's receptors, TLR4 and TREM-1, and showed that the presence of AIM altered eCIRP's binding to these receptors.
CONCLUSION: In male mice, gut I/R decreases AIM protein levels and mRNA expression in the lungs as well as AIM plasma concentration. AIM reduces eCIRP-induced pro-inflammatory cytokine production in macrophages, potentially by inhibiting eCIRP's binding to TLR4 and TREM-1. These findings suggest AIM is a promising therapeutic candidate in males with gut I/R.

Keywords:  Apoptosis inhibitor of macrophage; CD5L; Damage-Associated molecular pattern; Gut ischemia; Reperfusion injury

DOI:  https://doi.org/10.1186/s10020-025-01385-1
Exploration (Beijing). 2025 Oct;5(5): 20250127

Immunomodulatory Nanozymes Eradicate Intracellular Infections and Rescue Immunoparalysis for Treating Multidrug-Resistant Bacterial Sepsis.

Xuancheng Du, Zhenzhen Dong, Yan Yan, Yuan Gong, Meili Yuan, Chengtai Ma, Lingqi Xu, Yuanyuan Qu, Minhan Qu, Peng Pan, Weifeng Li, Wenyan Hao, Yingyi Yang, Xiangdong Liu, Mingwen Zhao, Zhenjiang Bai, Jiang Huai Wang, Jian Wang, Yong-Qiang Li, Huiting Zhou.

  Sepsis and their sequelae are the leading causes of death in intensive care units, with limited therapeutic options. Immunoparalysis plays a vital role in the pathophysiological progression of sepsis, leading to intracellular persistent infections and high mortality of septic patients. Eradicating intracellular infections and rescuing immunoparalysis are critical for sepsis management, yet effective tactics remain elusive. Here, we report immunomodulatory nanozymes (named PdIr@OMVs) that enable intracellular bacteria elimination and reinvigorate systemic innate-adaptive immune response during immunoparalysis to tackle multidrug-resistant (MDR) bacterial sepsis. The PdIr@OMVs are designed by encapsulating plasmonic PdIr nanocatalysts with immunostimulants of biocompatible bacterial outer membrane vesicles (OMVs). PdIr@OMVs exhibit unique localized surface plasmon response-enhanced peroxidase-like catalytic activity, and inherit the remarkable immunocyte-targeting capability and adjuvanticity of OMVs. We demonstrate that PdIr@OMVs not only potentiate the phagolysosomal killing effect of impaired macrophages via in situ catalysis to eradicate intracellular MDR bacteria and burst antigen release, but also allow rapid activation/maturation of dendritic cells to boost the presentation of bacterial antigen and orchestrate innate-adaptive immunity for rescuing immunoparalysis. In two immunocompromised mouse models of MDR bacterial sepsis, PdIr@OMVs collaboratively reduce bacterial burden and restore immune homeostasis, thereby circumventing organ damage and enabling the recovery of septic mice. Our work offers a promising therapeutic modality for sepsis and septic shock.

Keywords:  bacterial infections; immunosuppression; multidrug resistance; nanozymes; sepsis

DOI:  https://doi.org/10.1002/EXP.20250127