Nontranscriptional regulation of NLRP3 inflammasome signaling by IL-4

Abstract

Inflammasomes are cytosolic protein complexes that trigger caspase-1 activation and interleukin-1β (IL-1β) maturation in response to pathogen infection and danger associated molecular patterns (DAMPs). Of particular interest, many reports have demonstrated that NLRP3 is implicated in the development of auto-inflammatory or metabolic disorders including rheumatoid arthritis, gout, type II diabetes and atherosclerosis. However, the regulatory mechanism of NLRP3 inflammasome activation is still poorly characterized. Here we show that stimulation of macrophages with interleukin-4 (IL-4) inhibits NLRP3 inflammasome activation. The negative regulation of the NLRP3 inflammasome by IL-4 was not due to the reduced mRNA production of proinflammatory cytokines and NLRP3. Furthermore, the IL-4-mediated suppression of NLRP3 inflammasome signaling was independent of STAT6-dependent transcription and mitochondrial ROS. However, IL-4 modulated subcellular redistribution of NLRP3 into mitochondria upon NLRP3-activating stimulation. Our data collectively suggest that IL-4 could suppress NLRP3 inflammasome activation in a transcription-independent manner, thus providing an endogenous regulatory machinery to prevent excessive inflammasome activation.