Activation of the Toll-like receptor 4 (TLR4) by bacterial endotoxins in macrophages plays a crucial role in the pathogenesis of sepsis. However, the mechanism underlying TLR4 activation in macrophages is still not fully understood. Here, we reveal that upon lipopolysaccharide (LPS) stimulation, lysine acetyltransferase CBP is recruited to the TLR4 signalosome complex leading to increased acetylation of the TIR domains of the TLR4 signalosome. Acetylation of the TLR4 signalosome TIR domains significantly enhances signaling activation via NF-κB rather than IRF3 pathways. Induction of NF-κB signaling is responsible for gene expression changes leading to M1 macrophage polarization. In sepsis patients, significantly elevated TLR4-TIR acetylation is observed in CD16+ monocytes combined with elevated expression of M1 macrophage markers. Pharmacological inhibition of HDAC1, which deacetylates the TIR domains, or CBP play opposite roles in sepsis. Our findings highlight the important role of TLR4-TIR domain acetylation in the regulation of the immune responses in sepsis, and we propose this reversible acetylation of TLR4 signalosomes as a potential therapeutic target for M1 macrophages during the progression of sepsis.

中文翻译：

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TLR4-Mal-MyD88 复合物中 TIR 结构域的乙酰化调节脓毒症中的免疫反应。


巨噬细胞中细菌内毒素激活 Toll 样受体 4 （TLR4） 在脓毒症的发病机制中起着至关重要的作用。然而，巨噬细胞中 TLR4 激活的潜在机制仍不完全清楚。在这里，我们揭示了在脂多糖 （LPS） 刺激下，赖氨酸乙酰转移酶 CBP 被募集到 TLR4 信号体复合物中，导致 TLR4 信号体的 TIR 结构域乙酰化增加。TLR4 信号体 TIR 结构域的乙酰化通过 NF-κB 而不是 IRF3 通路显着增强信号激活。NF-κB 信号传导的诱导是导致 M1 巨噬细胞极化的基因表达变化的原因。在脓毒症患者中，在 CD16+ 单核细胞中观察到 TLR4-TIR 乙酰化显着升高，同时 M1 巨噬细胞标志物表达升高。HDAC1 的药理学抑制（使 TIR 结构域脱乙酰）或 CBP 在脓毒症中起相反的作用。我们的研究结果强调了 TLR4-TIR 结构域乙酰化在脓毒症免疫反应调节中的重要作用，并提出 TLR4 信号体的这种可逆乙酰化作为脓毒症进展过程中 M1 巨噬细胞的潜在治疗靶点。