ID: 36: MCPIP1/Regnase-1 is a negative feedback inhibitor regulating IL-17 signaling and inflammation

Abstract

IL-17A (IL-17) is a proinflammatory cytokine that mediates host defense against extracellular pathogens but also contributes to the pathogenesis of various autoimmune diseases. Despite advances in our understanding of IL-17 signal transduction mechanisms, it is far less clear how IL-17R activity is kept in check to prevent harmful bystander inflammation. In an effort to identify novel, physiologically relevant regulators of IL-17 signal transduction, we evaluated microarray data of IL-17RA-dependent genes that mediate antifungal immunity. We thus identified the gene Zc3h12a (encoding MCPIP1/Regnase-1) as a possible feedback restriction element. MCPIP1 is an endoribonuclease (RNase) that inhibits TLR signaling in part by degrading cytokine mRNA transcripts such as Il6 . Since IL-17 and TLR pathways share multiple target genes including Il6 , we investigated the role of MCPIP1 in IL-17 signal transduction. Here, we demonstrate that MCPIP1 is upregulated by IL-17 and serves as a potent feedback inhibitor of IL-17 signal transduction. IL-17 signaling inhibition required MCPIP1’s RNase activity, but not its deubiquitinase activity. In vivo , resistance to disseminated Candida albicans infection was enhanced in MCPIP1 haploinsufficient mice; resistance was reversed in an IL-17R-deficient background. Conversely, IL-17-dependent pathology in MCPIP1+/− mice was dramatically exacerbated during EAE and pulmonary inflammation. In vitro , MCPIP1 strongly inhibited the Lcn2 promoter activation by regulating the mRNA stability of the I κ B ζ transcription factor. Unexpectedly, MCPIP1 also degraded Il17ra and Il17rc mRNA, independently of the 3’ UTR. The cumulative impact of MCPIP1 on IL-6, I κ B ζ and possibly IL-17R subunits results in a biologically relevant inhibition of IL-17 signaling.