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J Immunol. 2018 Jul 1;201(1):167-182. doi: 10.4049/jimmunol.1701157. Epub 2018 May 23.

IL-36α from Skin-Resident Cells Plays an Important Role in the Pathogenesis of Imiquimod-Induced Psoriasiform Dermatitis by Forming a Local Autoamplification Loop.

Author information

1
Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
2
Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba, Chiba 260-8673, Japan; and.
3
Department of Dermatology, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-8670, Japan.
4
Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan; iwakura@rs.tus.ac.jp.

Abstract

IL-36α (gene symbol Il1f6), a member of the IL-36 family, is closely associated with inflammatory diseases, including colitis and psoriasis. In this study, we found that Il1f6-/- mice developed milder psoriasiform dermatitis upon treatment with imiquimod, a ligand for TLR ligand 7 (TLR7) and TLR8, whereas Il1f6-/- mice showed similar susceptibility to dextran sodium sulfate-induced colitis to wild-type mice. These effects were observed in both cohoused and separately housed conditions, and antibiotic treatment did not cancel the resistance of Il1f6-/- mice to imiquimod-induced dermatitis. Bone marrow (BM) cell transfer revealed that IL-36α expression in skin-resident cells is important for the pathogenesis of dermatitis in these mice. Following stimulation with IL-36α, the expression of Il1f6 and Il1f9 (IL-36γ), but not Il1f8 (IL-36β), was enhanced in murine BM-derived Langerhans cells (BMLCs) and murine primary keratinocytes but not in fibroblasts from mice. Upon stimulation with agonistic ligands of TLRs and C-type lectin receptors (CLRs), Il1f6 expression was induced in BMLCs and BM-derived dendritic cells. Furthermore, IL-36α stimulation resulted in significantly increased gene expression of psoriasis-associated Th17-related cytokines and chemokines such as IL-1α, IL-1β, IL-23, CXCL1, and CXCL2 in BMLCs and fibroblasts, and IL-1α, IL-1β, IL-17C, and CXCL2 in keratinocytes. Collectively, these results suggest that TLR/CLR signaling-induced IL-36α plays an important role for the development of psoriasiform dermatitis by enhancing Th17-related cytokine/chemokine production in skin-resident cells via a local autoamplification loop.

PMID:
29794016
DOI:
10.4049/jimmunol.1701157
[Indexed for MEDLINE]

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