title: Experimental atopic dermatitis depends on IL-33R signaling via MyD88 in dendritic cells.
abstract: Atopic dermatitis (AD) is a chronic Th2 type inflammatory skin disorder. Here we report that MyD88 signaling is crucial in the pathogenesis of experimental AD induced by vitamin D3 analog MC903. The clinical signs and inflammation caused by MC903 are drastically reduced in MyD88-/-mice with diminished eosinophil, neutrophil infiltration and Th2 cytokine expression. The biological effect of interleukin-1 (IL-1) family members relies on MyD88 signaling. We observed a strong upregulation of IL-1 family cytokine expression, including IL-1α, IL-1β, IL-33, IL-18, IL-36α, IL-36β, IL-36γ and IL-36Ra. Therefore, we asked which cytokine of the IL-1 family would be essential for MC903-induced AD syndrome. We find a significant reduction of AD in IL-33-/-and IL-33R/ST2-/-mice, only a minor reduction in double IL-1αβ-/-mice and no difference in IL-36R-/-and IL-36Ra-/-mice. IL-33 is expressed in keratinocytes, and MyD88 signaling in dendritic cells (DCs) is crucial for AD development as inflammation was drastically reduced in DC-specific MyD88-/-mice (CD11c-cre × MyD88-floxed). Taken together, the data demonstrate a critical role of MyD88 in DCs and of IL-33 signaling via ST2 in MC903-induced AD. These data suggest that IL-33/IL-33R may be a therapeutic target of AD.
authors.affiliation: Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS and University of Orleans, F-45071 Orleans-Cedex 2, France.|Shanghai Institute of Traumatology and Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Changwei
authors.initials: C
authors.lastname: Li
authors.affiliation: Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS and University of Orleans, F-45071 Orleans-Cedex 2, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maillet
authors.affiliation: Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS and University of Orleans, F-45071 Orleans-Cedex 2, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Mackowiak
authors.affiliation: Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS and University of Orleans, F-45071 Orleans-Cedex 2, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Viala
authors.affiliation: Novartis Institutes for Biomedical Research WSJ 386.11.48.38 4002, Basel, Switzerland.
authors.forename: Franco
authors.initials: F
authors.lastname: Di Padova
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR7104/Institut National de la Santé et de la Recherche Médicale U964/Université de Strasbourg, Illkirch, France.|University of Strasbourg Institute for Advanced Study, Strasbourg, France.|Freiburg Institute for Advanced Studies, Freiburg, Germany.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Artimmune SAS, rue Bouffon, 45071 Orleans-Cedex 2, France.
authors.forename: Dieudonnée
authors.initials: D
authors.lastname: Togbe
authors.affiliation: Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS and University of Orleans, F-45071 Orleans-Cedex 2, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Quesniaux
authors.affiliation: IDM, Institute of Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS and University of Orleans, F-45071 Orleans-Cedex 2, France.|Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D003876:Dermatitis, Atopic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D000072179:Interleukin-1 Receptor-Like 1 Protein; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D018123:Receptors, Interleukin; C055085:calcipotriene; D002117:Calcitriol