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

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 IκBζ transcription factor. Unexpectedly, MCPIP1 also degraded Il17ra and Il17rc mRNA, independently of the 3’ UTR. The cumulative impact of MCPIP1 on IL-6, IκBζ and possibly IL-17R subunits results in a biologically relevant inhibition of IL-17 signaling.