Sepsis-induced thrombocytopenia (SIT) is a widely accepted predictor of poor prognosis during sepsis, while the mechanism of SIT remains elusive. In this study, we revealed that SIT patients and septic mice exhibited higher levels of pro-inflammatory macrophages and phosphorylated BTK (p-BTK) expression in macrophages, which were closely correlated with platelet counts. Treatment with the BTK inhibitor, BGB-3111 in SIT mice resulted in enhanced production of megakaryocytes and platelets. Depletion of macrophages in SIT mice and coculture experiments further confirmed the critical role of macrophages in the improvement of platelet count induced by BGB-3111. By performing single-cell RNA sequencing on bone marrow-derived cells from SIT mice, we not only confirmed the connection between macrophages and megakaryocytes influenced by BTK but also identified a potential mediation through the Rap1 signaling pathway in macrophages. Subsequent experiments in macrophages demonstrated that inhibition of BTK signaling impeded the pro-inflammatory polarization of macrophages by targeting the Rap1/NF-κB signaling pathway. In conclusion, our study highlights the crucial role of macrophages in SIT, and inhibiting phosphorylation of BTK in macrophages may alleviate SIT through the Rap1/NF-κB signaling pathway.

中文翻译：

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在脓毒症诱导的血小板减少症中，由于 BTK/Rap1/NF-κB 通路的异常巨噬细胞极化导致巨核细胞生成受损。


脓毒症诱导的血小板减少症 （SIT） 是脓毒症期间预后不良的广泛接受预测指标，而 SIT 的机制仍然难以捉摸。在这项研究中，我们揭示了 SIT 患者和脓毒症小鼠在巨噬细胞中表现出更高水平的促炎巨噬细胞和磷酸化 BTK （p-BTK） 表达，这与血小板计数密切相关。在 SIT 小鼠中用 BTK 抑制剂 BGB-3111 治疗导致巨核细胞和血小板的产生增加。SIT 小鼠巨噬细胞耗竭和共培养实验进一步证实了巨噬细胞在 BGB-3111 诱导的血小板计数改善中的关键作用。通过对 SIT 小鼠的骨髓来源细胞进行单细胞 RNA 测序，我们不仅证实了巨噬细胞与受 BTK 影响的巨核细胞之间的联系，还确定了通过巨噬细胞中 Rap1 信号通路的潜在介导。随后在巨噬细胞中的实验表明，抑制 BTK 信号通过靶向 Rap1/NF-κB 信号通路来阻碍巨噬细胞的促炎极化。总之，我们的研究强调了巨噬细胞在 SIT 中的关键作用，抑制巨噬细胞中 BTK 的磷酸化可能通过 Rap1/NF-κB 信号通路缓解 SIT。