Non‐transcriptional regulation of NLRP3 inflammasome signaling by IL‐4

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Abstract
Th2 cytokine IL‐4 has been previously shown to suppress the production of proinflammatory cytokines in monocytes. However, the underlying molecular mechanism by which IL‐4 signaling antagonizes proinflammatory responses is poorly characterized. In particular, whether IL‐4 can modulate inflammasome signaling remains unknown. Here, we provide evidence that IL‐4 suppresses NLRP3‐dependent caspase‐1 activation and the subsequent IL‐1β secretion but does not inhibit absent in melanoma 2 (AIM2)‐ or NLRC4 (NOD‐like receptor family, CARD domain‐containing 4)‐dependent caspase‐1 activation in THP‐1 and mouse bone marrow‐derived macrophages. Upon lipopolysaccharide (LPS) or LPS/ATP stimulation, IL‐4 markedly inhibited the assembly of NLRP3 inflammasome, including NLRP3‐dependent ASC (apoptosis‐associated speck‐like protein containing a caspase recruitment domain) oligomerization, NLRP3‐ASC interaction and NLRP3 speck‐like oligomeric structure formation. The negative regulation of NLRP3 inflammasome by IL‐4 was not due to the impaired mRNA or protein production of NLRP3 and proinflammatory cytokines. Supporting this observation, IL‐4 attenuated NLRP3 inflammasome activation even in reconstituted NLRP3‐expressing macrophages in which NLRP3 expression is not transcriptionally regulated by TLR‐NF‐κB signaling. Furthermore, the IL‐4‐mediated suppression of NLRP3 inflammasome was independent of STAT6‐dependent transcription and mitochondrial reactive oxygen species (ROS). Instead, IL‐4 inhibited subcellular redistribution of NLRP3 into mitochondria and microtubule polymerization upon NLRP3‐activating stimulation. Our results 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.
Funding Information
  • National Research Foundation of Korea
  • Yonsei University College of Medicine (6‐2014‐0037)

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