In humans, blood Classical CD14+ monocytes contribute to host defense by secreting large amounts of pro-inflammatory cytokines. Their aberrant activity causes hyper-inflammation and life-threatening cytokine storms, while dysfunctional monocytes are associated with 'immunoparalysis', a state of immune hypo responsiveness and reduced pro-inflammatory gene expression, predisposing individuals to opportunistic infections. Understanding how monocyte functions are regulated is critical to prevent these harmful outcomes. We reveal platelets' vital role in the pro-inflammatory cytokine responses of human monocytes. Naturally low platelet counts in patients with immune thrombocytopenia or removal of platelets from healthy monocytes result in monocyte immunoparalysis, marked by impaired cytokine response to immune challenge and weakened host defense transcriptional programs. Remarkably, supplementing monocytes with fresh platelets reverses these conditions. We discovered that platelets serve as reservoirs of key cytokine transcription regulators, such as NF-κB and MAPK p38, and pinpointed the enrichment of platelet NF-κB2 in human monocytes by proteomics. Platelets proportionally restore impaired cytokine production in human monocytes lacking MAPK p38α, NF-κB p65, and NF-κB2. We uncovered a vesicle-mediated platelet-monocyte-propagation of inflammatory transcription regulators, positioning platelets as central checkpoints in monocyte inflammation.

中文翻译：

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血小板转录因子许可人类单核细胞的促炎细胞因子反应。


在人类中，血液经典 CD14+ 单核细胞通过分泌大量促炎细胞因子来促进宿主防御。它们的异常活性会导致过度炎症和危及生命的细胞因子风暴，而功能失调的单核细胞则与“免疫麻痹”有关，这是一种免疫反应低下和促炎基因表达减少的状态，使个体容易发生机会性感染。了解单核细胞功能如何调节对于预防这些有害结果至关重要。我们揭示了血小板在人类单核细胞促炎细胞因子反应中的重要作用。免疫性血小板减少症患者的血小板计数自然较低，或从健康单核细胞中去除血小板会导致单核细胞免疫麻痹，其特点是细胞因子对免疫挑战的反应受损和宿主防御转录程序减弱。值得注意的是，用新鲜血小板补充单核细胞可以逆转这些情况。我们发现血小板是关键细胞因子转录调节因子（例如 NF-κB 和 MAPK p38）的储存库，并通过蛋白质组学确定了血小板 NF-κB2 在人类单核细胞中的富集。血小板按比例恢复缺乏 MAPK p38α、NF-κB p65 和 NF-κB2 的人单核细胞中受损的细胞因子产生。我们发现了囊泡介导的炎症转录调节因子的血小板单核细胞增殖，将血小板定位为单核细胞炎症的中心检查点。