MCPIP1/Regnase is a negative feedback inhibitor of IL-17-mediated signaling and inflammation (CCR3P.200)

IL-17 came to prominence with the discovery of Th17 cells. IL-17 induces inflammatory pathology in autoimmunity and certain infections, and thus constraint of this pathway is an essential part of its regulation. However, to date our understanding of IL-17 signaling checkpoints remains quite limited....

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Published in:The Journal of immunology (1950) 2015-05, Vol.194 (1_Supplement), p.49-49.1
Main Authors: Gaffen, Sarah, Garg, Abhishek, Amatya, Nilesh, Chen, Kong, Cruz, Juan, Grover, Prerna, Whibley, Natasha, Conti, Heather, Hernandez Mir, Gerard, Childs, Erin, Smithgall, Thomas, Biswas, Partha, Kolls, Jay, McGeachy, Mandy, Kolattukudy, Pappachan
Format: Article
Language:English
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Summary:IL-17 came to prominence with the discovery of Th17 cells. IL-17 induces inflammatory pathology in autoimmunity and certain infections, and thus constraint of this pathway is an essential part of its regulation. However, to date our understanding of IL-17 signaling checkpoints remains quite limited. Here, we identify MCPIP1 (Regnase-1, Zc3h12a) as a novel negative feedback inhibitor of IL-17 signaling. IL-17 treatment of fibroblasts stimulated increased MCPIP1 expression, whereas MCPIP1 silencing enhanced IL-17-mediated signal transduction. Conversely, reconstitution of MCPIP1-/- cells restricted IL-17 signaling, which was dependent on the MCPIP1 endonuclease domain, not its deubiquitinase domain. In vivo, MCPIP1 deficiency enhanced IL-17-dependent autoimmunity and host resistance to infection. Namely, susceptibility to candidiasis was reduced in MCPIP1 haploinsufficient mice, whereas IL-17-dependent pathology in EAE and pulmonary inflammation was enhanced. In addition to its well-documented capacity to degrade cytokine mRNA transcripts such as Il6, we found that MCPIP1 regulates some, though not all, IL-17-dependent promoters. In addition, we identified a novel function for MCPIP1 in mediating decay of mRNA transcripts encoding inflammatory receptors, including IL-17R subunits, in a manner independent of their 3’ UTR elements. This is the first demonstration that MCPIP1 restricts IL-17R signal transduction, and that this enzyme regulates inflammatory receptor expression.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.194.Supp.49.1