Autophagy Induction Ameliorates Inflammatory Responses in Intestinal Ischemia–Reperfusion Through Inhibiting NLRP3 Inflammasome Activation

Abstract

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.

Activation of autophagy inhibits nucleotide‐binding oligomerization domain‐like receptor protein 3 inflammasome activation and attenuates myocardial ischemia‐reperfusion injury in diabetic rats

“…It has been reported that PINK1-Parkin-mediated mitochondrial autophagy played a protective role in CI-AKI by reducing NLRP3 inflammasome activation 38 . Autophagy, by inhibiting NLRP3 inflammasome activation, could alleviate intestinal I/RI and the inflammatory response 20 . The present study showed that autophagy in the myocardium of 8-week-old diabetic rats was significantly inhibited, accompanied by activation of NLRP3 inflammasome.…”

“…In addition, autophagy can also reduce inflammation by eliminating inflammatory stimuli, such as ROS, mitochondrial deoxyribonucleic acid or damaged organelles, to maintain homeostasis 17,18 . Previous observations found that autophagic activity can attenuate cerebral and intestinal I/RI by eliminating mitochondrial deoxyribonucleic acid and mitochondrial ROS, and inhibiting the activation of NLRP3 inflammasome 19,20 .…”

IL-37 Gene Modification Enhances the Protective Effects of Mesenchymal Stromal Cells on Intestinal Ischemia Reperfusion Injury

“…Previous studies have demonstrated that NLRP3 inflammasome involved in several ischemia reperfusion injury organ such as heart, liver, kidney and so on. Interestingly, little has been reported about the role of NLRP3 in intestinal ischemia-reperfusion injury until Wang et al identified that NLRP3 actually count in intestinal IRI [30]. Several studies suggested that targeting inhibiting NLRP3 inflammasome activation could alleviate ischemia reperfusion injury occurring in different organs [11-13, 31, 32].…”

IL-37 Gene Modification Enhances the Protective Effects of Mesenchymal Stromal Cells on Intestinal Ischemia Reperfusion Injury

“…Previous studies have demonstrated that NLRP3 inflammasome involved in several ischemia reperfusion injury organ such as heart, liver, kidney and so on. Interestingly, little has been reported about the role of NLRP3 in intestinal ischemia-reperfusion injury until Wang et al identified that NLRP3 actually count in intestinal IRI [30]. Several studies suggested that targeting inhibiting NLRP3 inflammasome activation could alleviate ischemia reperfusion injury occurring in different organs [7,12,13,31,32].…”