A role for mitochondria in NLRP3 inflammasome activation

Rongbi Zhou, Amir S, Yazdi, Philippe Menu & Jurg Tschopp Nature 2010;469:221-225.

Speaker: Yin-Chiou, Luo (羅尹秋)                                       Time:15:00~16:00, May.18, 2011

Commentator: Chiou-Feng Lin, Ph.D. (林秋烽老師)          Place: Room 601

Abstract

Various danger signals, including PAMPs, DAMPs and environmental irritants, activate the NLRP3 inflammasome that result in caspase-1 activation and release proinflammatory cytokines IL-1β and IL-18. Three major models for NLRP3 inflammasome activation are favored in the field. One of the models proposes that NLRP3 is activated by a common pathway of reactive oxygen species (ROS). However, the source of ROS is currently unclear. Previous studies indicated the main source of cellular ROS is mitochondria. Therefore the authors hypothesized that mitochondrial ROSmay be involved in NLRP3 activation. First, they demonstrated ROS derived from mitochondria cause NLRP3 inflammasome activation by using complex I or III of the mitochondrial respiratory chain inhibitors. In addition, they showed that inhibition of autophagy resulted in the accumulation of ROS-producing mitochondria and leads to spontaneous inflammasome activation. Since ROS are short-lived, the author hypothesized that NLRP3 should be localized in close to mitochondria. Treatment with NLRP3 inflammasome activators led to colocalization of both NLRP3 and ASC with mitochondria and mitochondria-associated ER membranes (MAMs). To directly demonstrate whether NLRP3 inflammasome activation depends on ROS production from respiring mitochondria, the authors inhibited the activity of voltage-dependent anion channels (VDAC) and found thatknockdown of VDAC impaired NLRP3 inflammasome activation. Thus, this study provides evidence for an unanticipated additional role of mitochondria in orchestration of the inflammatory response.

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