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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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Autores principales: Wannick, Melanie, Assmann, Julian C., Vielhauer, Jakob F., Offermanns, Stefan, Zillikens, Detlef, Sadik, Christian D., Schwaninger, Markus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102353/
https://www.ncbi.nlm.nih.gov/pubmed/30154797
http://dx.doi.org/10.3389/fimmu.2018.01890
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author Wannick, Melanie
Assmann, Julian C.
Vielhauer, Jakob F.
Offermanns, Stefan
Zillikens, Detlef
Sadik, Christian D.
Schwaninger, Markus
author_facet Wannick, Melanie
Assmann, Julian C.
Vielhauer, Jakob F.
Offermanns, Stefan
Zillikens, Detlef
Sadik, Christian D.
Schwaninger, Markus
author_sort Wannick, Melanie
collection PubMed
description 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(2)). Interestingly, neutrophils and monocytes expressed Hca2. To investigate whether the therapeutic effect of DMF in EBA is mediated by HCA(2), we administered oral DMF to Hca2-deficient mice (Hca2(−/−)) and wild-type littermates (Hca2(+/+)) and induced EBA. DMF treatment ameliorated skin lesions in Hca2(+/+) but not in Hca2(−/−) animals. These findings demonstrate that HCA(2) is a molecular target of DMF treatment in EBA and suggest that HCA(2) activation limits skin pathology by inhibiting the infiltration of neutrophils and monocytes into the skin.
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spelling pubmed-61023532018-08-28 The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation Wannick, Melanie Assmann, Julian C. Vielhauer, Jakob F. Offermanns, Stefan Zillikens, Detlef Sadik, Christian D. Schwaninger, Markus Front Immunol Immunology 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(2)). Interestingly, neutrophils and monocytes expressed Hca2. To investigate whether the therapeutic effect of DMF in EBA is mediated by HCA(2), we administered oral DMF to Hca2-deficient mice (Hca2(−/−)) and wild-type littermates (Hca2(+/+)) and induced EBA. DMF treatment ameliorated skin lesions in Hca2(+/+) but not in Hca2(−/−) animals. These findings demonstrate that HCA(2) is a molecular target of DMF treatment in EBA and suggest that HCA(2) activation limits skin pathology by inhibiting the infiltration of neutrophils and monocytes into the skin. Frontiers Media S.A. 2018-08-14 /pmc/articles/PMC6102353/ /pubmed/30154797 http://dx.doi.org/10.3389/fimmu.2018.01890 Text en Copyright © 2018 Wannick, Assmann, Vielhauer, Offermanns, Zillikens, Sadik and Schwaninger. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Wannick, Melanie
Assmann, Julian C.
Vielhauer, Jakob F.
Offermanns, Stefan
Zillikens, Detlef
Sadik, Christian D.
Schwaninger, Markus
The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation
title The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation
title_full The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation
title_fullStr The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation
title_full_unstemmed The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation
title_short The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation
title_sort immunometabolomic interface receptor hydroxycarboxylic acid receptor 2 mediates the therapeutic effects of dimethyl fumarate in autoantibody-induced skin inflammation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102353/
https://www.ncbi.nlm.nih.gov/pubmed/30154797
http://dx.doi.org/10.3389/fimmu.2018.01890
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