Autophagy induction ameliorates inflammatory responses in intestinal ischemiareperfusion through inhibiting NLRP3 inflammasome activation
Autophagy induction ameliorates inflammatory responses in intestinal ischemiareperfusion through inhibiting NLRP3 inflammasome activation
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自噬诱导通过抑制 NLRP3 炎症小体激活改善肠道缺血再灌注中的炎症反应
DOI：
10.1097/shk.0000000000001259
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发表时间：
2019
期刊：
影响因子：
3.1
通讯作者：
Tian Xiaofeng
中科院分区：
文献类型：
--
作者：
Wang Zishuo;Li Zhenlu;Feng Dongcheng;Zu Guo;Li Yang;Zhao Yan;Wang Guangzhi;Ning Shili;Zhu Jie;Zhang Feng;Yao Jihong;Tian Xiaofeng
肠缺血/再灌注（I/R）诱导的全身炎症导致多器官功能障碍综合征。以往的研究表明，NOD样受体蛋白（NLRP）3炎症体调节肠道炎症，但其病理生理机制尚不清楚。自噬是促进缺血性损伤后细胞存活的重要代谢机制。最近，基础自噬已被牵连在减轻广泛的炎症。然而，自噬在肠I/R诱导的炎性损伤中NLRP 3炎性小体活化中的作用仍然不确定。在本研究中，我们检测了肠I/R损伤小鼠中是否诱导NLRP 3炎性小体活化，其测量为增加的包含CARD水平的结肠炎相关斑点样蛋白、半胱天冬酶-1活性和白细胞介素-1 β（IL-1β）分泌。重要的是，体外结果表明，NLRP 3敲低降低了促炎细胞因子的产生，并增加了对缺氧/复氧（H/R）触发的炎症的抵抗力。随后，我们证明了自噬在体内抑制肠I/R诱导的NLRP 3炎性小体激活中的关键作用。此外，我们发现自噬的丧失激活了炎性小体介导的IL-1β分泌，这加剧了H/R损伤，而NLRP 3敲低逆转了这些作用。总的来说，这些结果直接涉及缺血性肠病中自噬和NLRP 3炎性体的稳态过程，并确定了肠I/R治疗干预的新途径。
Intestinal ischemia/reperfusion (I/R)-induced systemic inflammation leads to multiple organ dysfunction syndrome. Previous studies have indicated that the NOD-like receptor protein (NLRP) 3 inflammasome modulates intestinal inflammation; however, the pathophysiological mechanisms remain unclear. Autophagy is a critical metabolic mechanism that promotes cellular survival following ischemic injury. Recently, basal autophagy has been implicated in the alleviation of extensive inflammation. However, the role of autophagy in NLRP3 inflammasome activation in intestinal I/R-induced inflammatory injury remains undefined. In the present study, we examined whether NLRP3 inflammasome activation is induced in mice subjected to intestinal I/R injury, which is measured as increased apoptosis-associated speck-like protein containing a CARD levels, caspase-1 activity, and interleukin-1β (IL-1β) secretion. Importantly, the in-vitro results showed that NLRP3 knockdown decreases proinflammatory cytokine production and increases resistance to hypoxia/reoxygenation (H/R)-triggered inflammation. Subsequently, we demonstrated a critical role for autophagy in suppressing intestinal I/R-induced NLRP3 inflammasome activation in vivo. Furthermore, we showed that the loss of autophagy activates inflammasome-mediated IL-1β secretion, which aggravates H/R injury, and NLRP3 knockdown reverses these effects. Collectively, these results directly implicated the homeostatic process of autophagy and NLRP3 inflammasome in ischemic bowel disease and identified a novel pathway for therapeutic intervention in intestinal I/R.