MCPIP1/Regnase-1 restricts IL-17A- and IL-17C-dependent skin inflammation 1

• Published in: The Journal of immunology (1950) 2016-12, Vol.198 (2), p.767-775
• Main Authors: Monin, Leticia, Gudjonsson, Johann E., Childs, Erin E., Amatya, Nilesh, Xing, Xianying, Verma, Akash H., Coleman, Bianca M., Garg, Abhishek, Killeen, Meaghan, Mathers, Alicia, Ward, Nicole L., Gaffen, Sarah L.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1601551

The IL-17-family cytokines IL-17A and IL-17C drive the pathogenesis of psoriatic skin inflammation, and anti-IL-17A Abs were recently approved to treat human psoriasis. To date, little is known about mechanisms that restrain IL-17 cytokine-mediated signaling, particularly IL-17C. Here, we show that the endoribonuclease MCPIP1 (also known as Regnase-1) is markedly upregulated in human psoriatic skin lesions. Similarly, MCPIP1 was overexpressed in the imiquimod (IMQ)-driven mouse model of cutaneous inflammation. Mice with an MCPIP1 deficiency ( Zc3h12a +/− ) displayed no baseline skin inflammation, but they showed exacerbated pathology following IMQ treatment. Pathology in Zc3h12a +/− mice was associated with elevated expression of IL-17A- and IL-17C-dependent genes and also increased accumulation of neutrophils in skin. However, IL-17A and IL-17C expression was unaltered, suggesting that the increased inflammation in Zc3h12a +/− mice was due to enhanced downstream IL-17R signaling. Radiation chimeras demonstrated that MCPIP1 in non-hematopoietic cells is responsible for controlling skin pathology. Moreover, Zc3h12a +/− Il17ra −/− mice given IMQ showed almost no disease. To identify which IL-17RA ligand was essential, Zc3h12a +/− Il17a −/− and Zc3h12a +/− Il17c −/− mice were given IMQ; these mice had reduced but not fully abrogated pathology, indicating that MCPIP1 inhibits both IL-17A and IL-17C signaling. Confirming this hypothesis, Zc3h12a −/− keratinocytes showed increased responsiveness to IL-17A and IL-17C stimulation. Thus, MCPIP1 is a potent negative regulator of psoriatic skin inflammation through IL-17A and IL-17C. Moreover, MCPIP1 is the first described negative regulator of IL-17C signaling.