Trichostatin A modulates the macrophage phenotype by enhancing autophagy to reduce inflammation during polymicrobial sepsis
Trichostatin A modulates the macrophage phenotype by enhancing autophagy to reduce inflammation during polymicrobial sepsis
复制标题
曲古抑菌素 A 通过增强自噬来调节巨噬细胞表型，从而减少多种微生物败血症期间的炎症
DOI：
10.1016/j.intimp.2019.105973
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发表时间：
2019-12-01
影响因子：
5.6
通讯作者：
Shang, You
中科院分区：
文献类型：
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作者：
Cui, Shu-Nan;Chen, Zhao-Yuan;Shang, You
脓毒症是由宿主对感染的反应失调引起的危及生命的器官功能障碍综合征。巨噬细胞极化是脓毒症发病机制中的一个重要环节。最近的证据表明，自噬在炎症的不同阶段参与调节巨噬细胞的极化。在这里，我们研究了组蛋白去乙酰化酶（HDAC）抑制剂，抑制素A（TSA），是否促进巨噬细胞M2表型，通过增强自噬，以抵消盲肠结扎穿孔（CLP）小鼠模型中的过度炎症。TSA刺激增加了M2标记物（CD 206、CD 124和CD 23）标记的RAW 264.7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），也被称为mTOR抑制剂，意外地降低了M2标记的巨噬细胞的比例。然而，TSA治疗逆转了RAP诱导的CD 206标记的巨噬细胞减少。接下来，我们用自噬抑制剂MHY 1485或3-甲基腺嘌呤（3-MA）刺激不同组的RAW264.7细胞。在该过程的任何阶段抑制自噬都能抑制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管理促进腹腔巨噬细胞M2极化，增加LC 3 II的表达，衰减脓毒症诱导的器官（肺，肝和肾）损伤，并改变全身炎症细胞因子分泌。然而，3-MA取消了TSA对CLP小鼠的保护作用，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，以减少全身炎症，并最终改善患有多微生物败血症的小鼠的存活率。
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.