bims-traimu 2025-09-14 papers

Issue of 2025–09–14
seven papers selected by
Yantong Wan, Southern Medical University

Front Immunol. 2025 ;16 1652666

Editorial: Commending 20 years since the formal discovery of immune priming: the innate immune memory.

Keywords: adaptive immunity; ecological immunology; ecology; evolution; immune priming; parasites; specific immune memory; trained immunity

DOI: https://doi.org/10.3389/fimmu.2025.1652666

Elife. 2025 Sep 08. pii: RP104138. [Epub ahead of print]14

Aurora kinase A promotes trained immunity via regulation of endogenous S-adenosylmethionine metabolism.

Mengyun Li, Huan Jin, Yongxiang Liu, Zining Wang, Lin Li, Tiantian Wang, Xiaojuan Wang, Hongxia Zhang, Bitao Huo, Tiantian Yu, Shoujie Wang, Wei Zhao, Jinyun Liu, Peng Huang, Jun Cui, Xiaojun Xia.

Innate immune cells can acquire a memory phenotype, termed trained immunity, but the mechanism underlying the regulation of trained immunity remains largely elusive. Here, we demonstrate that inhibition of Aurora kinase A (AurA) dampens trained immunity induced by β-glucan. ATAC-seq and RNA-seq analysis reveal that AurA inhibition restricts chromatin accessibility of genes associated with inflammatory pathways such as JAK-STAT, TNF, and NF-κB pathways. Specifically, AurA inhibition promotes nuclear localization of FOXO3 and the expression of glycine N-methyltransferase (GNMT), a key enzyme responsible for S-adenosylmethionine (SAM) consumption. Metabolomic analysis confirms a reduction in SAM level upon AurA inhibition. As a result of SAM deficiency, trained mouse macrophages exhibit decreased H3K4me3 and H3K36me3 enrichment on gene regions of Il6 and Tnf. Additionally, the tumor inhibition effect of β-glucan is notably abolished by AurA inhibition. Together, our findings identify an essential role of AurA in regulating trained immunity via a methylation-dependent manner by maintaining endogenous SAM levels through the mTOR-FOXO3-GNMT axis.

Keywords: Aurora kinase A; FOXO3; GNMT; S-adenosylmethionine; epigenetics; immunology; inflammation; mouse; trained immunity

DOI: https://doi.org/10.7554/eLife.104138

Cell Immunol. 2025 Sep 06. pii: S0008-8749(25)00111-X. [Epub ahead of print]417 105025

Divergent metabolic rewiring shapes altered innate immunity.

Mohua Liu, Xiao Wang, Xiaoya Qu, Yao Wang, Xihui Shen, Lei Xu.

Both trained immunity (TRIM) and endotoxin tolerance (ET) initiate similar metabolic reprogramming characterized by enhanced glycolysis following an initial stimulus. However, TRIM exhibited heightened immune activation upon restimulation, whereas ET showed suppressed innate immune response. This divergence is attributed to distinct metabolic intermediates accumulated after the initial stimulation. In TRIM, metabolites like fumarate and glutamine derivatives accumulate, reinforcing pro-inflammatory epigenetic modifications. Conversely, ET is characterized by increased itaconate and lactate levels, promoting anti-inflammatory epigenetic changes and metabolic paralysis. This review highlights metabolic intermediates as key regulators of innate immune fate decisions, presenting avenues for targeted immune modulation.

Keywords: Endotoxin tolerance (ET); Fumarate; Itaconate; Mevalonate pathway; Trained immunity (TRIM)

DOI: https://doi.org/10.1016/j.cellimm.2025.105025

Cardiovasc Res. 2025 Sep 09. pii: cvaf158. [Epub ahead of print]

Toll-like receptor 4 induces trained innate immune tolerance in the heart in a model of stress-induced cardiomyopathy.

Kenji Rowel Q Lim, Junedh Amrute, Attila Kovacs, Abhinav Diwan, David L Williams, Douglas L Mann.

AIMS: Although the ability of the heart to adapt to environmental stress has been studied extensively, the molecular and cellular mechanisms responsible for cardioprotection are not yet fully understood. In this study, we sought to elucidate these mechanisms for cytoprotection using a model of stress-induced cardiomyopathy.
METHODS AND RESULTS: We administered Toll-like receptor (TLR) agonists or diluent to wild-type mice and assessed for cardioprotection against injury from a high intraperitoneal dose of isoproterenol (ISO) administered 7 days later. Cardioprotective effects were analyzed through serum cardiac troponin I levels, immune profiling via flow cytometry, echocardiography, and multiomic single-nuclei RNA/ATAC sequencing. Pretreatment with the TLR4 agonist lipopolysaccharide (LPS), but not TLR1/2 or TLR3 agonists, conferred cardioprotection, as demonstrated by reduced cardiac troponin I leakage, decreased inflammation, preserved cardiac structure and function, and improved survival. Remarkably, LPS-induced tolerance was reversed by β-glucan treatment. Multiomic analysis showed that LPS-tolerized hearts had greater chromatin accessibility and upregulated gene expression versus hearts treated with LPS and β-glucan (reverse-tolerized). LPS tolerance was associated with upregulation of interferon response pathways across various cell types, including cardiac myocytes and stromal cells. Blocking both type 1 and 2 interferon signaling eliminated LPS-induced tolerance against ISO, while pretreatment with recombinant type 1 and 2 interferons conferred cardiac protection. Multiomic sequencing further revealed enhanced cytoprotective signaling in interferon-treated hearts. Analysis of cell-cell communication networks indicated increased autocrine signaling by cardiac myocytes, as well as greater paracrine signaling between stromal cells and myeloid cells, in LPS-tolerized versus reverse-tolerized hearts.
CONCLUSIONS: LPS pretreatment confers cardiac protection against ISO-induced injury through TLR4-mediated type 1 and 2 interferon signaling, consistent with trained innate immune tolerance. The observation that LPS-induced protection in cardiac myocytes involves both cell-autonomous and non-cell-autonomous mechanisms underscores the complexity of innate immune tolerance in the heart, warranting further investigation into this cardioprotective phenotype.

Keywords: Toll-like receptor 4; interferon; tolerance; trained innate immunity

DOI: https://doi.org/10.1093/cvr/cvaf158

Transplant Direct. 2025 Sep;11(9): e1835

Potential Impact of Extracorporeal Photopheresis on Trained Immunity and Organ Transplant Acceptance.

Clémentine Tocco, Jordi Ochando.

Extracorporeal photopheresis (ECP) is a well-established, safe, and effective immunomodulatory therapy currently used in clinics to decrease T cell-mediated immunity in various disorders, including autoimmune diseases and chronic rejection in organ transplantation. Although the ECP procedure has been shown to induce apoptotic cells that are reintroduced into the patient at the end of the treatment, the precise tolerogenic mechanisms mediated by ECP are not fully understood. Previous in vitro studies have demonstrated that early apoptotic cells express annexins on their cell surface, which suppress myeloid cell activation on stimulation with bacterial lipopolysaccharide through Toll-like receptors. Mechanistically, annexins prevent the upregulation of costimulatory molecules (CD40 and CD86) and decrease the secretion of proinflammatory cytokines (tumor necrosis factor and interferon-γ) through nuclear factor kappa B signaling pathways, altogether inhibiting antigen-specific T-cell responses in vivo. In human and mouse bone marrow-derived macrophages, binding of annexin to Dectin-1, a c-type lectin receptor, promotes peripheral tolerance through the spleen tyrosine kinase signaling pathway and NADPH oxidase 2 downstream activation. In animal models, the synergistic activation of Dectin-1 and Toll-like receptor 4 by damage-associated molecular patterns in graft-infiltrating monocytes leads to the induction of trained immunity. Because trained immunity prevents long-term allograft survival in organ transplant recipients, we hypothesize pretreatment with ECP represents a potential unexplored therapeutic option to favor transplantation tolerance. Specifically, ECP may serve as a prophylactic therapy to prevent trained immunity in contexts involving the activation of the Dectin-1 pathway.

DOI: https://doi.org/10.1097/TXD.0000000000001835

Nat Metab. 2025 Sep 10.

In vivo itaconate tracing reveals degradation pathway and turnover kinetics.

Hanna F Willenbockel, Alexander T Williams, Alfredo Lucas, Mack B Reynolds, Emeline Joulia, Maureen L Ruchhoeft, Birte Dowerg, Pedro Cabrales, Christian M Metallo, Thekla Cordes.

Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized by tricarboxylic acid (TCA) metabolism downstream of TLR signalling. Itaconate-based treatment strategies are under investigation to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13C itaconate tracing in male mice, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine and fuels TCA cycle metabolism specifically in the liver and kidneys. Our results further reveal that itaconate is converted into acetyl-CoA, mesaconate and citramalate. Itaconate administration also influences branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase and methylmalonyl-CoA mutase activity in male rats and mice. Our findings uncover a previously unknown aspect of itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.

DOI: https://doi.org/10.1038/s42255-025-01363-1

Cell. 2025 Sep 03. pii: S0092-8674(25)00972-9. [Epub ahead of print]

IL-25-induced memory type 2 innate lymphoid cells enforce mucosal immunity.

Victor S Cortez, Sara Viragova, Satoshi Koga, Meizi Liu, Claire E O'Leary, Roberto R Ricardo-Gonzalez, Andrew W Schroeder, Nathan Kochhar, Dedeepya Vaka, Dario Boffelli, Ophir D Klein, Michael S Diamond, Hong-Erh Liang, Richard M Locksley.

Adaptation of intestinal helminths to vertebrates involved the evolution of strategies to attenuate host tissue damage to support parasite reproduction and dissemination of offspring to the environment. Helminths initiate the IL-25-mediated tuft cell-type 2 innate lymphoid cell (ILC2) circuit that enhances barrier protection of the host, although viable parasites can target and limit this pathway. We used IL-25 alone to create small intestinal adaptation, marked by anatomic and immunologic changes that persisted months after induction. Adaptation was associated with heightened resistance to barrier pathogens, including in the lung, and was enforced by transcriptionally and epigenetically modified effector-memory ILC2s distinct from those described by innate "training"; epithelial stem cells remained unaltered. Despite requiring IL-25 for induction, effector-memory ILC2s maintained an activated state in the absence of multiple alarmins and supported mucosal resilience while avoiding adverse sensitization to chronic inflammation, revealing a pathway for deploying innate immune cells to coordinate a distributed mucosal defense.

Keywords: IL-25; ILC2s; alarmins; epigenetics; epithelial stem cells; helminth infection; innate memory; small intestines; tissue adaptation

DOI: https://doi.org/10.1016/j.cell.2025.08.017