Abstract:
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.
摘要:
在人类中,血液经典的CD14+单核细胞通过分泌大量的促炎细胞因子来促进宿主防御。它们的异常活性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与“免疫麻痹”有关,免疫低反应性和促炎基因表达降低的状态,易患机会性感染的个体。了解单核细胞功能如何被调节对于防止这些有害结果至关重要。我们揭示了血小板在人单核细胞的促炎细胞因子反应中的重要作用。患有免疫性血小板减少症或从健康单核细胞中去除血小板的患者的自然低血小板计数导致单核细胞免疫麻痹。以细胞因子对免疫攻击的反应受损和宿主防御转录程序减弱为标志。值得注意的是,用新鲜血小板补充单核细胞逆转了这些情况。我们发现血小板作为关键细胞因子转录调节因子的储库,如NF-κB和MAPKp38,并通过蛋白质组学确定了血小板NF-κB2在人单核细胞中的富集。血小板按比例恢复缺乏MAPKp38α的人单核细胞中受损的细胞因子产生,NF-κBp65和NF-κB2。我们发现了炎症转录调节因子的囊泡介导的血小板-单核细胞传播,定位血小板作为单核细胞炎症的中心检查点。