The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation

The drug dimethyl fumarate (DMF) is in clinical use for the treatment of psoriasis and multiple sclerosis. In addition, it has recently been demonstrated to ameliorate skin pathology in mouse models of pemphigoid diseases, a group of autoimmune blistering diseases of the skin and mucous membranes. H...

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Bibliographic Details
Published in:	Frontiers in immunology Vol. 9; p. 1890
Main Authors:	Wannick, Melanie, Assmann, Julian C, Vielhauer, Jakob F, Offermanns, Stefan, Zillikens, Detlef, Sadik, Christian D, Schwaninger, Markus
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 14-08-2018
Subjects:	autoimmune blistering skin disease G protein-coupled receptor Immunology immunomodulatory therapy neutrophils pemphigoid disease G protein-coupled receptor pemphigoid disease immunomodulatory therapy autoimmune blistering skin disease neutrophils
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Summary:	The drug dimethyl fumarate (DMF) is in clinical use for the treatment of psoriasis and multiple sclerosis. In addition, it has recently been demonstrated to ameliorate skin pathology in mouse models of pemphigoid diseases, a group of autoimmune blistering diseases of the skin and mucous membranes. However, the mode of action of DMF in inflammatory skin diseases has remained elusive. Therefore, we have investigated here the mechanisms by which DMF improves skin pathology, using the antibody transfer model of bullous pemphigoid-like epidermolysis bullosa acquisita (EBA). Experimental EBA was induced by transfer of antibodies against collagen VII that triggered the infiltration of immune cells into the skin and led to inflammatory skin lesions. DMF treatment reduced the infiltration of neutrophils and monocytes into the skin explaining the improved disease outcome in DMF-treated animals. Upon ingestion, DMF is converted to monomethyl fumarate that activates the hydroxycarboxylic acid receptor 2 (HCA ). Interestingly, neutrophils and monocytes expressed . To investigate whether the therapeutic effect of DMF in EBA is mediated by HCA , we administered oral DMF to -deficient mice ( ) and wild-type littermates ( ) and induced EBA. DMF treatment ameliorated skin lesions in but not in animals. These findings demonstrate that HCA is a molecular target of DMF treatment in EBA and suggest that HCA activation limits skin pathology by inhibiting the infiltration of neutrophils and monocytes into the skin.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by: Angelo Valerio Marzano, Università degli Studi di Milano, Italy Reviewed by: Alex Ortega Loayza, Oregon Health & Science University, United States; Jillian M. Richmond, University of Massachusetts Medical School, United States These authors have contributed equally to this work. Specialty section: This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology
ISSN:	1664-3224 1664-3224
DOI:	10.3389/fimmu.2018.01890