BACKGROUND:While platelets have well-studied hemostatic functions, platelets are immune cells that circulate at the interface between the vascular wall and white blood cells. The physiological implications of these constant transient interactions are poorly understood. Activated platelets induce and amplify immune responses, but platelets may also maintain immune homeostasis in healthy conditions, including maintaining vascular integrity and T helper cell differentiation, meaning that platelets are central to both immune responses and immune quiescence. Clinical data have shown an association between low platelet counts (thrombocytopenia) and immune dysfunction in patients with sepsis and extracorporeal membrane oxygenation, further implicating platelets as more holistic immune regulators, but studies of platelet immune functions in nondisease contexts have had limited study.METHODS:We used in vivo models of thrombocytopenia and in vitro models of platelet and monocyte interactions, as well as RNA-seq and ATAC-seq (assay for transposase-accessible chromatin with sequencing), to mechanistically determine how resting platelet and monocyte interactions immune program monocytes.RESULTS:Circulating platelets and monocytes interact in a CD47-dependent manner to regulate monocyte metabolism, histone methylation, and gene expression. Resting platelet-monocyte interactions limit TLR (toll-like receptor) signaling responses in healthy conditions in an innate immune training-like manner. In both human patients with sepsis and mouse sepsis models, thrombocytopenia exacerbated monocyte immune dysfunction, including increased cytokine production.CONCLUSIONS:Thrombocytopenia immune programs monocytes in a manner that may lead to immune dysfunction in the context of sepsis. This is the first demonstration that sterile, endogenous cell interactions between resting platelets and monocytes regulate monocyte metabolism and pathogen responses, demonstrating platelets to be immune rheostats in both health and disease.

中文翻译：

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血小板减少症独立导致单核细胞免疫功能的变化

背景：虽然血小板具有充分研究的止血功能，但血小板是在血管壁和白细胞之间的界面循环的免疫细胞。人们对这些持续瞬时相互作用的生理影响知之甚少。活化的血小板可诱导和放大免疫反应，但血小板还可以在健康条件下维持免疫稳态，包括维持血管完整性和 T 辅助细胞分化，这意味着血小板对于免疫反应和免疫静止至关重要。临床数据显示，脓毒症和体外膜氧合患者的低血小板计数（血小板减少症）与免疫功能障碍之间存在关联，进一步表明血小板是更全面的免疫调节剂，但非疾病背景下血小板免疫功能的研究有限。我们使用血小板减少症的体内模型和血小板与单核细胞相互作用的体外模型，以及 RNA-seq 和 ATAC-seq（转座酶可及染色质测序分析），从机械上确定静息血小板和单核细胞如何与免疫程序单核细胞相互作用结果：循环血小板和单核细胞以 CD47 依赖性方式相互作用，调节单核细胞代谢、组蛋白甲基化和基因表达。静息血小板-单核细胞相互作用以类似于先天免疫训练的方式限制健康条件下的 TLR（Toll 样受体）信号反应。在脓毒症人类患者和小鼠脓毒症模型中，血小板减少症加剧了单核细胞免疫功能障碍，包括细胞因子产生增加。结论：血小板减少症免疫程序对单核细胞的编程可能会导致脓毒症情况下的免疫功能障碍。这是首次证明静息血小板和单核细胞之间无菌的内源性细胞相互作用调节单核细胞代谢和病原体反应，证明血小板在健康和疾病中都是免疫变阻器。