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.
*Department of General Surgery, Second Hospital of Dalian Medical University, Dalian, China
†Department of Emergency General Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
‡Department of Pharmacology, Dalian Medical University, Dalian, China
Address reprint requests to Xiaofeng Tian, PhD, Department of General Surgery, The Second Hospital of Dalian Medical University, 116023, Dalian, China. E-mail: email@example.com
Received 22 April, 2018
Revised 9 May, 2018
Accepted 27 August, 2018
Zishuo Wang and Zhenlu Li contributed equally to this work.
Financial Support: This work was financially supported by grants from the National Natural Science Foundation of China (No. 81501699, No.81671954 and No. 81600411).
The authors report no conflicts of interest.