title: Non-transcriptional regulation of NLRP3 inflammasome signaling by IL-4.
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.
authors.affiliation: Department of Microbiology, Brain Korea 21 PLUS Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Inhwa
authors.initials: I
authors.lastname: Hwang
authors.affiliation: Department of Microbiology, Brain Korea 21 PLUS Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jungmin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Microbiology, Brain Korea 21 PLUS Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sujeong
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Microbiology, Brain Korea 21 PLUS Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Eun
authors.initials: E
authors.lastname: Ju Lee
authors.affiliation: Graduate School of Medical Science and Engineering, Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors.forename: Seung-Hyo
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Fernandes-Alnemri
authors.affiliation: Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Emad S
authors.initials: ES
authors.lastname: Alnemri
authors.affiliation: Department of Microbiology, Brain Korea 21 PLUS Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Je-Wook
authors.initials: JW
authors.lastname: Yu
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D042541:Intracellular Space; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011485:Protein Binding; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D058847:Inflammasomes; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017382:Reactive Oxygen Species; D050800:STAT6 Transcription Factor; D015847:Interleukin-4; D020170:Caspase 1