title: MCPIP1/Regnase-1 Restricts IL-17A- and IL-17C-Dependent Skin Inflammation.
abstract: 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. Little is known about mechanisms that restrain IL-17 cytokine-mediated signaling, particularly IL-17C. In this article, we show that the endoribonuclease MCP-1-induced protein 1 (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, as well as with 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 nonhematopoietic 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 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, to our knowledge, MCPIP1 is the first described negative regulator of IL-17C signaling.
authors.affiliation: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15260.
authors.forename: Leticia
authors.initials: L
authors.lastname: Monin
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Johann E
authors.initials: JE
authors.lastname: Gudjonsson
authors.affiliation: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15260.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Childs
authors.affiliation: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15260.
authors.forename: Nilesh
authors.identifier: 0000-0002-7942-1742
authors.initials: N
authors.lastname: Amatya
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Xianying
authors.identifier: 0000-0003-4227-6868
authors.initials: X
authors.lastname: Xing
authors.affiliation: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15260.
authors.forename: Akash H
authors.identifier: 0000-0002-5985-5201
authors.initials: AH
authors.lastname: Verma
authors.affiliation: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15260.
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Coleman
authors.affiliation: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15260.
authors.forename: Abhishek V
authors.initials: AV
authors.lastname: Garg
authors.affiliation: Department of Dermatology, University of Pittsburgh, Pittsburgh, PA 15260; and.
authors.forename: Meaghan
authors.initials: M
authors.lastname: Killeen
authors.affiliation: Department of Dermatology, University of Pittsburgh, Pittsburgh, PA 15260; and.
authors.forename: Alicia
authors.identifier: 0000-0001-6931-8605
authors.initials: A
authors.lastname: Mathers
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, OH 44106.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Ward
authors.affiliation: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15260; Sarah.Gaffen@pitt.edu.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gaffen
mesh_terms: D000818:Animals; D003872:Dermatitis / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000276:immunology; D015603:Keratinocytes / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011565:Psoriasis / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D012260:Ribonucleases / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology*
chemical_list: D020381:Interleukin-17; D014157:Transcription Factors; D012260:Ribonucleases; C510646:ZC3H12A protein, human; C541320:Zc3h12a protein, mouse