bims-traimu 2025-03-09 papers

Issue of 2025–03–09
five papers selected by
Yantong Wan, Southern Medical University

Sci Adv. 2025 Mar 07. 11(10): eads0105

Trained immunity causes myeloid cell hypercoagulability.

Aisling M Rehill, Seán McCluskey, Anna E Ledwith, Tristram A J Ryan, Betül Ünlü, Gemma Leon, Hugo Charles-Messance, Edmund H Gilbert, Paula Klavina, Emily A Day, Judith Coppinger, Jamie M O'Sullivan, Corrina McMahon, James S O'Donnell, Annie M Curtis, Luke A J O'Neill, Frederick J Sheedy, Roger J S Preston.

The pathogenic basis for increased thrombotic risk in individuals with inflammatory diseases is poorly understood. Myeloid cell "trained immunity" describes persistent innate immune cell memory arising from prior exposure to an inflammatory stimulus, leading to an enhanced immune response to subsequent unrelated stimuli. We identify enhanced myeloid cell prothrombotic activity as a maladaptive consequence of trained immunity. Lipopolysaccharide (LPS) stimulation of macrophages trained previously with β-glucan or heme exhibited significantly enhanced procoagulant activity compared to macrophages stimulated with LPS alone, which was mediated by enhanced acid sphingomyelinase-mediated tissue factor decryption. Furthermore, splenic monocytes isolated from β-glucan-trained mice revealed enhanced procoagulant activity up to 4 weeks after β-glucan administration compared to monocytes from control mice over the same time period. Moreover, hematopoietic progenitor cells and bone marrow interstitial fluid from β-glucan-trained mice had enhanced procoagulant activity compared to control mice. Trained immunity and associated metabolic perturbations may therefore represent an opportunity for targeted intervention in immunothrombotic disease development.

DOI: https://doi.org/10.1126/sciadv.ads0105

Dev Cell. 2025 Feb 19. pii: S1534-5807(25)00063-2. [Epub ahead of print]

Innate immune training of osteoclastogenesis promotes inflammatory bone loss in mice.

We previously demonstrated that long-term trained immunity (TRIM) involves adaptations that imprint innate immune memory in long-lived myelopoiesis precursors and their progeny, monocytes/macrophages and neutrophils, which thereby acquire enhanced responsiveness to future challenges. Here, we show that a distinct component of myeloid biology, osteoclastogenesis, can also undergo innate immune training. Indeed, β-glucan-induced TRIM was associated with an increased osteoclastogenesis bias in the bone marrow and an expansion of monocytes/osteoclast progenitors in the periphery, resulting in aggravated severity of experimental periodontitis and arthritis. In the setting of trained inflammatory osteoclastogenesis, we observed transcriptomic rewiring in synovial myeloid cells of arthritic mice, featuring prominent upregulation of the transcription factor melanogenesis-associated transcription factor (MITF). Adoptive transfer of splenic monocytes from β-glucan-trained mice to naive recipients exacerbated arthritis in the latter in a strictly MITF-dependent manner. Our findings establish trained osteoclastogenesis as a maladaptive component of TRIM and potentially provide therapeutic targets in inflammatory bone loss disorders.

Keywords: inflammatory bone loss; innate immune memory; monocytes; osteoclastogenesis; trained immunity

DOI: https://doi.org/10.1016/j.devcel.2025.02.001

Front Pharmacol. 2025 ;16 1546191

The lower rate of bone and joint infection in patients with open extremity fractures associated with vaccination prior to injury: a propensity-matched cohort study.

Wencheng Hu, Saiyu Shi, Junqing Lin, Tao Gao, Junjie Shen, Yi Sun, Haifeng Wei, Xianyou Zheng.

Background: Vaccines could strengthen the innate immune system in addition to conferring protection against their target pathogen via vaccine-induced immunomodulation, a phenomenon termed trained immunity. The purpose of the present study was to determine whether vaccination prior to injury is associated with a lower rate of bone and joint infections (BJIs) in patients with open extremity fractures.
Methods: Patients with open extremity fractures treated at one hospital between January 2010 and December 2019 were identified. Incidental vaccine recipients and control cohorts were matched in a 1:1 ratio using propensity scores based on age, sex, anatomical location of the fracture, Gustilo-Anderson classification, body mass index (BMI), and diagnosis of diabetes. The primary endpoint was BJIs within 1 year after initial injury. Secondary outcomes were neutrophil counts and serum C-reactive protein (CRP) levels within 24 h of admission. Logistic or linear regression was performed to control for potential confounding factors when comparing primary and secondary outcomes.
Results: Vaccine inoculation history was successfully collected from 6,338 patients, with only 83 patients receiving an incidental vaccine inoculation within 3 months before injury. After propensity score matching, demographic and clinical factors were well-balanced between cohorts (all standardized differences >0.1). After controlling for potential confounders, patients in the vaccine group were at a lower risk of BJIs after open extremity fractures (vaccine, 2/83 [2.4%]; control, 10/83 [12.0%), p = 0.011). Levels of circulating neutrophils and CRP were slightly increased in the vaccine group.
Conclusion: Vaccine inoculation is associated with the lower BJI rate after open extremity fractures, and vaccinated patients might have a more robust immune response against bacterial challenges in terms of neutrophil and CRP levels after injury. Future prospective cohort studies and clinical trials are warranted to evaluate this finding definitively.
Clinical Trail registration: http://www.chictr.org.cn/usercenter.aspx, identifier ChiCTR2000041093.

Keywords: bone and joint infection; fracture; propensity-matched cohort study; trained immunity; vaccine

DOI: https://doi.org/10.3389/fphar.2025.1546191

Cancer Lett. 2025 Feb 26. pii: S0304-3835(25)00154-5. [Epub ahead of print]616 217590

Leukemia confers a durable imprint on healthy hematopoietic stem and progenitor cells.

Ding-Wen Chen, Julie M Schrey, Eric K Wafula, Jian-Meng Fan, Sarah E Adams, Deanne M Taylor, Peter Kurre.

Recent models of infection and experimental inflammation reveal that hematopoietic stem and progenitor cells (HSPCs) can generate a memory of the exposure. While the acute inflammatory activity rapidly resolves, cells acquire a heightened capacity to respond to subsequent stimulation. Inflammation is also a constitutive feature of cancer, including hematologic malignancies. Here, we adapt a translationally relevant model of acute myeloid leukemia (AML) to determine if inflammation in the bone marrow (BM) niche durably reprograms resident healthy HSPCs. To simulate the onset of malignancy and the subsequent remission, we generated hematopoietic chimera composed of healthy HSPCs and HSPCs bearing an inducible oncogenic human MLL-AF9 translocation expression cassette, a validated model of AML. Results show that the exposure to AML blasts in the BM leaves healthy HSPCs with transcriptomic changes and a shift to glycolytic metabolism during experimental remission. A secondary challenge of AML-experienced animals results in gene expression changes in inflammatory and metabolic pathways. These modified responses coincide with altered chromatin accessibility in AML-experienced HSPCs. Altogether, our observations provide first evidence for the durable inflammatory reprogramming of healthy HSPCs in the cancer microenvironment.

DOI: https://doi.org/10.1016/j.canlet.2025.217590

Sci Adv. 2025 Mar 07. 11(10): eads4957

Citrulline regulates macrophage metabolism and inflammation to counter aging in mice.

Zhangdan Xie, Moubin Lin, Beizi Xing, Hongmiao Wang, Haosong Zhang, Zimu Cai, Xinyu Mei, Zheng-Jiang Zhu.

Metabolic dysregulation and altered metabolite concentrations are widely recognized as key characteristics of aging. Comprehensive exploration of endogenous metabolites that drive aging remains insufficient. Here, we conducted an untargeted metabolomics analysis of aging mice, revealing citrulline as a consistently down-regulated metabolite associated with aging. Systematic investigations demonstrated that citrulline exhibited antiaging effects by reducing cellular senescence, protecting against DNA damage, preventing cell cycle arrest, modulating macrophage metabolism, and mitigating inflammaging. Long-term citrulline supplementation in aged mice yielded beneficial effects and ameliorated age-associated phenotypes. We further elucidated that citrulline acts as an endogenous metabolite antagonist to inflammation, suppressing proinflammatory responses in macrophages. Mechanistically, citrulline served as a potential inhibitor of mammalian target of rapamycin (mTOR) activation in macrophage and regulated the mTOR-hypoxia-inducible factor 1α-glycolysis signaling pathway to counter inflammation and aging. These findings underscore the significance of citrulline deficiency as a driver of aging, highlighting citrulline supplementation as a promising therapeutic intervention to counteract aging-related changes.

DOI: https://doi.org/10.1126/sciadv.ads4957