Institute of Clinical Medicine Research, Zhejiang Provincial People's Hospital of Hangzhou Medical College, Hangzhou, China.
Yantai Peninsular Cancer Center, Binzhou Medical University, Yantai, China.
EMBO J. 2024 Nov;43(21):4954-4983. doi: 10.1038/s44318-024-00237-8. Epub 2024 Sep 18.
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.
细菌内毒素通过巨噬细胞中的 Toll 样受体 4（TLR4）的激活在脓毒症发病机制中起着关键作用。然而，TLR4 在巨噬细胞中的激活机制仍不完全清楚。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，导致 TLR4 信号体的 TIR 结构域的乙酰化增加。TLR4 信号体 TIR 结构域的乙酰化通过 NF-κB 途径而非 IRF3 途径显著增强信号激活。NF-κB 信号的诱导负责导致 M1 巨噬细胞极化的基因表达变化。在脓毒症患者中，在 CD16+单核细胞中观察到 TLR4-TIR 乙酰化显著升高，同时 M1 巨噬细胞标志物的表达升高。组蛋白去乙酰化酶 1（HDAC1）的药理学抑制，该酶使 TIR 结构域去乙酰化，或 CBP 在脓毒症中发挥相反的作用。我们的发现强调了 TLR4-TIR 结构域乙酰化在脓毒症免疫反应调节中的重要作用，我们提出 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。
