Background/Purpose: IL-17 cytokines have emerged as drivers of autoimmunity. Indeed, the IL-17A-targeting antibody secukinumab (Cosentyx) was recently approved for treatment of plaque psoriasis, and shows efficacy in psoriatic arthritis and ankylosing spondylitis. IL-17 family members signal through a dimeric receptor composed of a common subunit, IL-17RA, and a variant co-receptor. Both IL-17A and IL-17C have been implicated in psoriasis pathology, but while IL-17A signals through IL-17RA and IL-17RC, IL-17C is reported to act through an IL-17RA/IL-17RE heterodimer. To date, little is known about the regulatory mechanisms that control the amplitude of inflammation mediated by IL-17 cytokines, particularly in the context of autoimmunity. Not surprisingly, numerous mechanisms have evolved to restrict IL-17 signaling to limit bystander tissue damage. The endoribonuclease Regnase-1 [also known as MCP1-Induced Protein 1 (MCPIP1), encoded by Zc3h12a] is a key regulator of inflammation. We previously showed that Regnase-1 downregulates IL-17A signaling, including expression of IL-6 and IkBz. Consequently, Regnase-1-deficient mice had exacerbated CNS inflammation in the experimental autoimmune encephalomyelitis model. Here, we assessed the impact of MCPIP1 in a murine model of psoriasis, and verified its presence in human psoriatic lesions.

Methods: Psoriatic inflammation was induced by application of imiquimod (IMQ). Zc3h12a^+/-, Il17ra^-/-, Il17c^-/-, Il17re^-/-and intercrossed mice or littermates were subjected to IMQ-induced psoriasis for 1-5 days. Disease was assessed by measurement of ear thickening, H&E staining of skin sections, immune cell infiltration by flow cytometry, and gene expression by qPCR. Bone marrow chimeras were made by adoptive transfer into irradiated recipients. De-identified skin biopsies were stained for Regnase-1 by IHC.

Results: During IMQ-induced inflammation, Zc3h12a mRNA was elevated in mouse skin. Consistently, ZC3H12A was more highly expressed in human lesional skin than in non-lesional or healthy skin biopsies. Consistent with its recognized role as a feedback inhibitor, mice deficient for Regnase-1 (Zc3h12a^+/-) showed more dermal inflammation following IMQ-induced psoriasis induction than littermate controls, whereas Il17ra^-/- mice were fully resistant to disease. Genes associated with Regnase-1-induced inflammation included prototypical IL-17 target genes such as Il6 and Lcn2. Bone marrow chimeras indicated that the inhibitory activity of Regnase-1 in IMQ-psoriasis was restricted to the non-hematopoietic compartment, which was also consistent with an IL-17-dependent pathogenesis. Further evidence to support this model was the finding that Zc3h12a^+/-Il17ra^-/- mice were fully protected from disease. Surprisingly, neither Zc3h12a^+/-Il17c^-/- nor Zc3h12a^+/-Il17re^-/-mice were protected, suggesting that Regnase-1 activity is restricted to IL-17A in this setting.

Conclusion: Regnase-1 negatively regulates IL-17A but not IL-17C or IL-17RE in the context of autoimmune skin inflammation. Regnase-1 is overexpressed in active dermal inflammation, but is nonetheless insufficient to control disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/negative-regulation-of-il-17-receptor-signaling-by-regnase-1-limits-immunopathology-in-a-mouse-model-of-psoriatic-skin-disease/