bims-traimu 2025-07-27 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–07–27
twelve papers selected by
Yantong Wan, Southern Medical University

Metabolic dysregulation of trained immunity in immune aging and the impact of dietary patterns.
Cues of Trained Immunity in Multiple Sclerosis Macrophages.
A dual nature of γδ T cell immune memory responses.
Bioengineering approaches to trained immunity: Physiologic targets and therapeutic strategies.
Critical Role of IL1R2-ENO1 Interaction in Inhibiting Glycolysis-Mediated Pyroptosis for Protection Against Lethal Sepsis.
Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis.
Dopamine as an endogenous regulator of innate immunity in sepsis.
LPS mediates cuproptosis and inflammation in THP-1 macrophages through HKDC1.
Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections.
Tolerance Induced by Porphyromonas gingivalis Altered Inflammatory Responses in Mice.
Dynamic changes in chromatin accessibility within one month of mouse intracerebral hemorrhage.
Rhamnose alleviates the proinflammatory response during endotoxemia via the CEACAM1/LGALS9-p38 axis.

Am J Physiol Cell Physiol. 2025 Aug 01. 329(2): C456-C470

Metabolic dysregulation of trained immunity in immune aging and the impact of dietary patterns.

Andra Grigorescu, Anca-Lelia Riza, Ioana Streata, Mihai G Netea.

  Trained immunity (TRIM) is the process through which the innate immune system undergoes memory-like epigenetic and metabolic reprogramming following an earlier infectious challenge. Trained immunity can be induced, in a similar fashion to microbial structures, by various endogenous compounds: oxidized low-density lipoproteins, lipoprotein(a), glucose and uric acid, and monosodium urate. Lipids, glucose, and protein metabolic dysfunction have the potential to perpetuate a proinflammatory feedback loop through the induction of maladaptive trained immunity programs, as shown in cardiovascular diseases, diabetes, and hyperuricemia. Molecular mechanisms leading to TRIM are susceptible to homeostatic disruptions of advanced age, and maladaptive TRIM may be the link between immune aging and age-associated pathologies. The present review discusses the current knowledge on metabolic pathways in adaptive and maladaptive trained immunity and its deleterious consequences of inappropriate activation during aging. Finally, we discuss how several dietary patterns modulate immunometabolism and influence trained immunity in aging.

Keywords:  immune aging; inflammaging; nutrition; trained immunity

DOI:  https://doi.org/10.1152/ajpcell.00153.2025
Cells. 2025 Jul 10. pii: 1054. [Epub ahead of print]14(14):

Cues of Trained Immunity in Multiple Sclerosis Macrophages.

Elisa Popa, Hélène Cheval, Violetta Zujovic.

  Multiple sclerosis (MS) is a complex autoimmune disease with both genetic and environmental influences, yet its underlying mechanisms remain only partially understood. In this review, we compile evidence suggesting that trained immunity-a form of innate immune memory-may play a crucial role in the autoimmune component of MS. By examining key findings from immunology, neuroinflammation, and MS pathophysiology, we explore how innate immune cells, particularly monocytes and macrophages, could contribute to disease onset and progression through persistent pro-inflammatory responses. Understanding the impact of trained immunity in MS could open new avenues for therapeutic strategies targeting the innate immune system.

Keywords:  epigenetic; inflammation; macrophages; metabolism; multiple sclerosis; trained immunity

DOI:  https://doi.org/10.3390/cells14141054
Elife. 2025 Jul 23. pii: e104887. [Epub ahead of print]14

A dual nature of γδ T cell immune memory responses.

Tsz Kin Suen, Burcu Al, Alice Scarpa, Anca Dorhoi, Mihai G Netea, Katarzyna Placek.

  Immune memory was considered for decades an exclusive hallmark of the adaptive immune response. However, recent studies have revealed that innate immune cells can also 'recall' information of a primary insult during infection or vaccination and deploy robust antigen-agonistic immune reactivity upon secondary challenge. This de-facto innate immune memory response is designated as 'trained immunity'. γδ T cells are unconventional T cells that possess unique immunologic features of both adaptive and innate immunity. Their immune memory responses to various bacterial and viral agents were originally described to be of an adaptive immune nature. Nevertheless, growing evidence shows that γδ T cells can also mount antigen-independent memory responses resembling trained immunity. In this review, we discuss the dual nature of immune memory responses of γδ T cells and provide insights into their important role in protection against bacterial, viral, and parasitic infections in humans and animals.

Keywords:  gamma delta T cells; immune memory; immunology; inflammation; trained immunity

DOI:  https://doi.org/10.7554/eLife.104887
Elife. 2025 Jul 23. pii: e106339. [Epub ahead of print]14

Bioengineering approaches to trained immunity: Physiologic targets and therapeutic strategies.

Hannah Riley Knight, Marie Kim, Nisha Kannan, Hannah Taylor, Hailey Main, Emily Azcue, Aaron Esser-Kahn.

  Trained immunity presents a unique target for modulating the immune response against infectious and non-infectious threats to human health. To address the unmet need for training-targeted therapies, we explore bioengineering methods to answer research questions and address clinical applications. Current challenges in trained immunity include self-propagating autoinflammatory disease, a lack of controllable cell and tissue specificity, and the unintentional induction of training by known drugs and diseases. The bioengineering tools discussed in this review (nanotherapeutics, biomechanical modulation, cellular engineering, and machine learning) could address these challenges by providing additional avenues to modulate and interrogate trained immunity. The preferential activation of peripheral or central training has not yet been achieved and could be accessed using nanoparticle systems. Targeted delivery of training stimuli using nanocarriers can enrich the response in various cell and organ systems, while also selectively activating peripheral training in the local tissues or central trained immunity in bone marrow progenitor cells. Beyond chemical- or pathogen-based activation of training, force-based cues, such as interaction with mechanoreceptors, can induce trained phenotypes in many cell types. Mechanotransduction influences immune cell activation, motility, and morphology and could be harnessed as a tool to modulate training states in next-generation therapies. For known genetic and epigenetic mediators of trained immunity, cellular engineering could precisely activate or deactivate programs of training. Genetic engineering could be particularly useful in generating trained cell-based therapies like chimeric antigen receptor (CAR) macrophages. Finally, machine learning models, which are rapidly transforming biomedical research, can be employed to identify signatures of trained immunity in pre-existing datasets. They can also predict protein targets for previously identified inducers of trained immunity by modeling drug-protein or protein-protein interactions in silico. By harnessing the modular techniques of bioengineering for applications in trained immunity, training-based therapies can be more efficiently translated into clinical practice.

Keywords:  bioengineering; biomechanics; cellular engineering; immunology; inflammation; machine learning; nanotherapeutics; trained immunity

DOI:  https://doi.org/10.7554/eLife.106339
Adv Sci (Weinh). 2025 Jul 24. e02297

Critical Role of IL1R2-ENO1 Interaction in Inhibiting Glycolysis-Mediated Pyroptosis for Protection Against Lethal Sepsis.

Chuyi Tan, Han Ma, Jespar Chen, Gaifeng Ma, Alok Jha, Sipin Tan, Yaxi Zhu, Meidong Liu, Ke Liu, Xianzhong Xiao, Monowar Aziz, Huan Chen, Ping Wang, Huali Zhang.

  Immune cell metabolic reprogramming toward glycolysis is vital for sepsis defense. While interleukin 1 receptor 2 (IL1R2) acts as a decoy receptor for IL1α/β, its potential impact on cell metabolism and death during sepsis remains unclear. This study observed elevated plasma soluble IL1R2 (sIL1R2) levels in septic patients and mice. In pyroptotic macrophages, reduced intracellular IL1R2 expression led to its release extracellularly. Proteomic screening identified enolase 1 (ENO1), a key glycolysis enzyme, as the binding partner of IL1R2 in macrophages. IL1R2 suppresses ENO1 activity to inhibit glycolysis, gasdermin D (GSDMD)-mediated pyroptosis, and inflammation in macrophages. IL1R2-deficient mice exhibited heightened susceptibility to sepsis, with increased inflammation, organ injury, and mortality. Notably, ENO1 inhibition reduced inflammation, organ injury, and improved survival rates in septic mice. The study reveals that IL1R2 interacts with ENO1 to inhibit glycolysis-mediated pyroptosis and inflammation in sepsis, suggesting the IL1R2-ENO1 interaction as a promising therapeutic target of sepsis.

Keywords:  IL1R2; enolase 1; glycolysis; macrophages; pyroptosis; sepsis

DOI:  https://doi.org/10.1002/advs.202502297
Cell Rep. 2025 Jul 21. pii: S2211-1247(25)00803-4. [Epub ahead of print]44(8): 116032

Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis.

Louise Nuyttens, Marah Heyerick, Geike Heremans, Elise Moens, Maxime Roes, Céline Van Dender, Liesbet De Bus, Johan Decruyenaere, Jan Dewaele, Jolien Vandewalle, Claude Libert.

  Sepsis, killing 11 million people yearly, is associated with increased production of lactate-a metabolite mechanistically linked to mortality-complicating glucose administration in sepsis. To understand the mechanism behind hyperlactatemia, we applied the cecal ligation and puncture (CLP) model and studied all pyruvate processing routes in liver mitochondria during acute sepsis. Our data suggest that mitochondrial pyruvate-driven respiration is nearly nonexistent in sepsis, not due to insufficient pyruvate uptake or carboxylation, but due to a dysfunctional pyruvate dehydrogenase complex (PDC). Septic mitochondria compensate via glutamate-mediated tricarboxylic acid (TCA) anaplerosis, simultaneously converting some pyruvate into alanine via enhanced mitochondrial glutamic pyruvate transaminase (GPT2) activity. PDC dysfunction is not caused by PDC inactivation per se but by a shortage of its cofactor, thiamine pyrophosphate (TPP). TPP supplementation restores pyruvate oxidation and protects mice from sepsis. TPP also allows safe glucose administration in mice, leading to a robust TPP-plus-glucose therapy.

Keywords:  CP: Metabolism; CP: Microbiology; lactate; mitochondria; pyruvate; sepsis; thiamine

DOI:  https://doi.org/10.1016/j.celrep.2025.116032
Front Immunol. 2025 ;16 1625368

Dopamine as an endogenous regulator of innate immunity in sepsis.

Haichao Wang, Rui Kang, Daolin Tang.

  Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, presents a major clinical challenge. While the complex interplay of inflammatory mediators and immune cells during sepsis is increasingly understood, the role of neurotransmitters, particularly dopamine, in modulating the innate immune response is emerging as a crucial area of investigation. Dopamine, traditionally recognized for its role in the central nervous system, acts as an endogenous regulator of innate immunity, significantly influencing the course and outcome of sepsis. In this mini-review, we highlight our recent finding of dopamine's critical role in regulating aconitate decarboxylase 1 (ACOD1) in sepsis.

Keywords:  CD274; aconitate decarboxylase 1; dopamine; innate immunity; sepsis

DOI:  https://doi.org/10.3389/fimmu.2025.1625368
Acta Biochim Biophys Sin (Shanghai). 2025 Jul 22.

LPS mediates cuproptosis and inflammation in THP-1 macrophages through HKDC1.

Langlin Ou, Zitong Meng, Jian Mei, Hao Yuan, Xiangrui Zhu, Xiaoying Wang, Ao Shen, Zhaosi Wang, Lixin Zhang, Song Wang, Yingli Chen, Xiangming Pang, Yuxiang Liu, Yadong Xu, Cui Ma.

  Cuproptosis is a recently identified form of copper-driven cell death characterized by the aggregation of acylated proteins and proteotoxic stress in the mitochondrial tricarboxylic acid cycle, which plays a role in inflammation. Recent studies suggest that hexokinase structural domain protein 1 (HKDC1), a fifth hexokinase, is involved in regulating mitochondrial function. However, the role of HKDC1 in cuproptosis and LPS-induced macrophage inflammation remains unclear. Here, we assess macrophage plasticity using CCK8 viability assays and phagocytosis activity experiments in an in vitro inflammatory model of THP-1 cells. We measure the levels of inflammatory factors and cuproptosis-related proteins using western blot analysis and RT-qPCR. Additionally, we examine the expression and localization of the HKDC1 protein using ChIP-qPCR and immunofluorescence staining. We find that LPS promotes the expressions of inflammatory factors and decreases cuproptosis levels in THP-1-derived macrophages while also activating glycolysis and inducing the expression of HKDC1 via the Toll-like receptor 4 (TLR4) receptor. We further demonstrate that HKDC1 knockdown inhibits glycolysis and induces cuproptosis. Mechanistically, we provide the first evidence that LPS promotes the binding of Yin Yang 1 (YY1) to the HKDC1 promoter, thereby regulating HKDC1 transcription. HKDC1 interacts with heat shock cognate B (HSCB) and ferredoxin 1 (FDX1), leading to increased intracellular copper levels and subsequent cuproptosis. HKDC1 knockdown in vivo alleviates acute sepsis by activating copper-dependent cell death pathways. Collectively, our findings suggest that LPS mitigates cuproptosis and promotes inflammation via HKDC1, suggesting a new cuproptosis-dependent anti-inflammatory strategy.

Keywords:  HKDC1; LPS; cuproptosis; glycolysis; inflammation

DOI:  https://doi.org/10.3724/abbs.2025089
Immunity. 2025 Jul 12. pii: S1074-7613(25)00286-9. [Epub ahead of print]

Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections.

Marco Di Gioia, Valentina Poli, Piao J Tan, Roberto Spreafico, Anne Chu, Alex G Cuenca, Zhongyang Wu, Mehdi Benamar, Laura Pandolfi, Federica Meloni, Fatemeh Askarian, Jason Hsiao, Elizaveata Borroum, Victor Nizet, Philip L S M Gordts, Joseph L Witztum, Talal A Chatila, Janet Chou, Xu Zhou, James R Springstead, Ivan Zanoni.

  Phagocytes initiate immunity to invading microorganisms by detecting pathogen-associated molecular patterns via pattern recognition receptors. Pathogen encounter and consequent activation of the immune system cause tissue damage and the release of host-derived damage-associated molecular patterns, contributing to shape immunity. However, how self-derived factors are sensed by phagocytes and impact the immune response remains poorly understood. Here, we demonstrated that host-derived oxidized phospholipids (oxPLs) are formed after microbial encounter in both mice and humans. oxPLs exacerbated inflammation without affecting pathogen burden. Mechanistically, oxPLs bound and inhibited AKT, potentiating the methionine cycle and the activity of the epigenetic writer EZH2. EZH2 epigenetically dampened the pluripotent anti-inflammatory cytokine IL-10, contributing to the death of the host. Overall, we found that host-derived oxPLs set the balance between protective and detrimental antimicrobial responses and that they can be prophylactically or therapeutically targeted to protect the host against deranged inflammation and immunopathology.

Keywords:  ARDS; DAMP; PAMP; PRR; damage-associated molecular pattern; epigenetic; macrophages; pathogen-associated molecular pattern; pattern recognition receptor; sepsis

DOI:  https://doi.org/10.1016/j.immuni.2025.06.017
Mol Oral Microbiol. 2025 Jul 23. e70002

Tolerance Induced by Porphyromonas gingivalis Altered Inflammatory Responses in Mice.

Miao Yu, Wen-Bo Qian, Yuan-Chun Fang, Yang Chen, Qiao Zhou, Ying Sun.

  Tolerance refers to a hyporesponsiveness toward repeated stimulations with bacteria and their virulence factors, which might exist in the development of periodontitis. To identify the roles of tolerance induced by Porphyromonas gingivalis (P. gingivalis) in periodontitis, an original tolerized mice model was established by high-dose of oral P. gingivalis inoculation following a primary infection. The alveolar bone loss of maxillae was detected by Micro-CT. The infiltration of neutrophils and macrophages, and macrophage polarization were detected by IHC and flow cytometry, respectively. Residual P. gingivalis in subgingival plaque with and without macrophage/neutrophil depletion was measured by real-time PCR. Moreover, a real-time PCR chip and bioinformatic analysis were then employed to explore the cytokine expression profiles in gingivae. The abundance of TNF-α, Toll-like receptor 2 (TLR2), and TLR4 were further verified by western blot. In comparison with the non-tolerance group, TNF-α protein levels, alveolar bone loss, and the infiltration of neutrophils and macrophages in the tolerance group were significantly suppressed (p < 0.05), while the quantities of residual P. gingivalis in subgingival plaque were increased (p < 0.05). Moreover, the depletion of macrophages by liposomal clodronate weakened the inhibitory effect of tolerance, as evidenced by the lack of differences in the quantities of residual bacteria between the tolerance and non-tolerance groups (p > 0.05). Macrophages in gingivae of tolerized mice were more likely to polarize into M2 type. In addition, the expressions of cytokines related to neutrophil and macrophage infiltration and recruitment and the protein levels of TLR2 and TLR4 were decreased in tolerized mice (p < 0.05). Tolerance induced by repeated P. gingivalis stimulations suppressed inflammatory responses in periodontal tissues, and the established periodontal tolerance model provided a reliable tool for the further study on periodontal tolerance in vivo.

Keywords:  Porphyromonas gingivalis; inflammation; mice; periodontal; tolerance

DOI:  https://doi.org/10.1111/omi.70002
iScience. 2025 Jul 18. 28(7): 112815

Dynamic changes in chromatin accessibility within one month of mouse intracerebral hemorrhage.

Rong Xiang, Kang OuYang, Junmin Wang, Zhan Chen, Jin Tao, Xinru Zhang, Houlian Zhang, Zhiyun Li, Luyao Wang, Ruoqi Ding, Chuanyu Liu, Jun Xie, Yong Hou, Jian Wang, Longqi Liu, Mingyue Wang.

  Intracerebral hemorrhage (ICH) is a severe stroke subtype associated with high mortality and disability. Understanding the molecular and cellular mechanisms behind ICH is vital for developing effective therapeutic interventions. We utilized a single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) to profile changes in chromatin accessibility over the first month following ICH in murine models. We examined 262,506 cells, identifying 77,978 upregulated and 35,023 downregulated candidate cis-regulatory elements (cCREs) across days 1, 3, 7, 14, and 28. Our results revealed disruptions in multiple super-enhancers in microglia and macrophages, along with a transition of reactive astrocytes from a protective to a neurotoxic state. We also observed a significant upregulation of genes involved in hypoxia response and lipid metabolism within the remyelination pathways post-ICH. This study provides crucial insights into the epigenetic changes that occur following ICH, laying a solid foundation for future research and potential therapeutic interventions.

Keywords:  genomics

DOI:  https://doi.org/10.1016/j.isci.2025.112815
Acta Biochim Biophys Sin (Shanghai). 2025 Jul 24.

Rhamnose alleviates the proinflammatory response during endotoxemia via the CEACAM1/LGALS9-p38 axis.

Rongjuan Wei, Tao Zhong, Ke Deng, Xianglong Zhang, Dongping Li, Meiling Chen, Ping Chang, Peng Wu, Zhanguo Liu.

  Gut microbiota plays an important role in orchestrating the host immune response. We previously reported that gut microbiota-derived rhamnose enhances the phagocytosis of macrophages, upon which we further asked whether rhamnose has modulatory effects on inflammation. Here, we show that, in an LPS-induced endotoxic mouse model, plasma rhamnose levels are increased. This bacteria-derived sugar alone does not impact inflammatory cytokine homeostasis or cause organ damage. In contrast, it is able to alleviate endotoxin-induced systemic inflammation and organ damage. Mechanistically, in macrophages in vitro, rhamnose binds to the V39, D40, and T101 sites of carcinoembryonic antigen-associated cell adhesion molecule 1 (CEACAM1), subsequently promoting the interaction between CEACAM1 and galectin 9 (LGALS9), which increases the protein level of dual-specificity protein phosphatase 1 (DUSP1). This inhibits p38 phosphorylation and thus attenuates the LPS-triggered expressions of proinflammatory factors. Collectively, our results suggest that rhamnose signals via the CEACAM1/LGALS9-p38 axis, which suppresses endotoxemia-associated inflammation, and that rhamnose is a candidate anti-inflammatory agent for the control of infection-induced organ damage.

Keywords:  CEACAM1; endotoxemia; infection; p38; rhamnose

DOI:  https://doi.org/10.3724/abbs.2025109