Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Int Immunopharmacol. 2019 Dec;77:105973. doi: 10.1016/j.intimp.2019.105973. Epub 2019 Oct 31.
Sepsis is a syndrome of life-threatening organ dysfunction caused by dysregulated host responses to infection. Macrophage polarization is a key process involved in the pathogenesis of sepsis. Recent evidence has demonstrated that autophagy participates in the regulation of macrophage polarization in different phases of inflammation. Here, we investigated whether trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, promotes the macrophage M2 phenotype by enhancing autophagy to counteract excessive inflammation in a cecal ligation and puncture (CLP) mouse model. TSA stimulation increased the proportions of M2 marker (CD206, CD124 and CD23)-labeled RAW264.7 macrophages. Furthermore, with increasing TSA doses, autophagy was enhanced gradually. Interestingly, the autophagy activator rapamycin (Rap), also known as an mTOR inhibitor, unexpectedly decreased the proportions of M2 marker-labeled macrophages. However, TSA treatment reversed the Rap-induced decreases in CD206-labeled macrophages. Next, we stimulated different groups of RAW264.7 cells with the autophagy inhibitors MHY1485 or 3-methyladenine (3-MA). Inhibition of autophagy at any stage in the process suppressed TSA-induced macrophage M2 polarization, but the effect was not associated with mTOR activity. In vivo, TSA administration promoted peritoneal macrophage M2 polarization, increased LC3 II expression, attenuated sepsis-induced organ (lung, liver and kidney) injury, and altered systemic inflammatory cytokine secretion. However, 3-MA abolished the protective effects of TSA in CLP mice and decreased the number of M2 peritoneal macrophages. Therefore, TSA promotes the macrophage M2 phenotype by enhancing autophagy to reduce systemic inflammation and ultimately improves the survival of mice with polymicrobial sepsis.
脓毒症是一种危及生命的器官功能障碍综合征，由宿主对感染的失调反应引起。巨噬细胞极化是脓毒症发病机制中的一个关键过程。最近的证据表明，自噬参与了不同炎症阶段的巨噬细胞极化调节。在这里，我们研究了组蛋白去乙酰化酶（HDAC）抑制剂曲古抑菌素 A（TSA）是否通过增强自噬来促进巨噬细胞 M2 表型，从而抵消盲肠结扎穿孔（CLP）小鼠模型中过度的炎症反应。TSA 刺激增加了 M2 标志物（CD206、CD124 和 CD23）标记的 RAW264.7 巨噬细胞的比例。此外，随着 TSA 剂量的增加，自噬逐渐增强。有趣的是，自噬激活剂雷帕霉素（Rap），也称为 mTOR 抑制剂，出人意料地降低了 M2 标志物标记的巨噬细胞的比例。然而，TSA 处理逆转了 Rap 诱导的 CD206 标记巨噬细胞减少。接下来，我们用自噬抑制剂 MHY1485 或 3-甲基腺嘌呤（3-MA）刺激不同组的 RAW264.7 细胞。在自噬过程的任何阶段抑制自噬都抑制了 TSA 诱导的巨噬细胞 M2 极化，但这种作用与 mTOR 活性无关。在体内，TSA 给药促进腹腔巨噬细胞 M2 极化，增加 LC3 II 表达，减轻脓毒症引起的器官（肺、肝和肾）损伤，并改变全身炎症细胞因子的分泌。然而，3-MA 消除了 TSA 在 CLP 小鼠中的保护作用，并减少了 M2 腹腔巨噬细胞的数量。因此，TSA 通过增强自噬来促进巨噬细胞 M2 表型，从而减少全身炎症反应，最终提高多微生物脓毒症小鼠的生存率。
