Authors: Yingying Han,1,2,3,12 Javier Mora,1,4,12 Arnaud Huard,1 Priscila da Silva,1 Svenja Wiechmann,5,6 Mateusz Putyrski,6 Christian Schuster,1 Eiman Elwakeel,1 Guangping Lang,7 Anica Scholz,1 Tatjana Scholz,8 Tobias Schmid,1 Natasja de Bruin,6 Pierre Billuart,9 Carlo Sala,10,11 Harald Burkhardt,6,8 Michael J. Parnham,6 Andreas Ernst,5,6 Bernhard Brune, € 1,6 and Andreas Weigert1,13,*

Issue: Cell Reports VOLUME 27, ISSUE 3, P835-846.E5, APRIL 16, 2019



Summary


Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or gd T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon gd T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress gd T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by gd T cells. Our findings indicate a role for IL-38 in the regulation of gd T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease.


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1- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany
2- Special Key Laboratory of Oral Diseases Research, Higher Education Institutions of Guizhou Province, Zunyi Medical University,
563006 Zunyi, Guizhou, China
3- School of Stomatology, Zunyi Medical University, 563006 Zunyi, Guizhou, China
4- Faculty of Microbiology, University of Costa Rica, 2060 San Jose´ , Costa Rica
5- Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, Faculty of Medicine, Goethe-University Frankfurt,
60590 Frankfurt am Main, Germany
6- Branch for Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME,
60590 Frankfurt, Germany
7- Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, 07745 Jena, Germany
8- Division of Rheumatology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
9- Institut Cochin, Institut National de la Sante´ et de la Recherche Me´ dicale U1016, Centre National de la Recherche Scientifique UMR8104,
Universite´ Paris Descartes, Paris 75014, France
10- National Research Council Neuroscience Institute, 20129 Milan, Italy
11- Department of Medical Biotechnology and Translational Medicine, Universita` degli Studi di Milano, 20129 Milan, Italy
12- These authors contributed equally
13- Lead Contact