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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| Published in: | Frontiers in immunology Vol. 9; p. 1890 |
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| Main Authors: | , , , , , , |
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14-08-2018
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| Abstract | 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. |
|---|---|
| AbstractList | 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. 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 (HCA2). Interestingly, neutrophils and monocytes expressed Hca2. To investigate whether the therapeutic effect of DMF in EBA is mediated by HCA2, 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 HCA2 is a molecular target of DMF treatment in EBA and suggest that HCA2 activation limits skin pathology by inhibiting the infiltration of neutrophils and monocytes into the skin. 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 (HCA2). Interestingly, neutrophils and monocytes expressed Hca2. To investigate whether the therapeutic effect of DMF in EBA is mediated by HCA2, 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 HCA2 is a molecular target of DMF treatment in EBA and suggest that HCA2 activation limits skin pathology by inhibiting the infiltration of neutrophils and monocytes into the skin. 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. |
| Author | Wannick, Melanie Assmann, Julian C Offermanns, Stefan Vielhauer, Jakob F Sadik, Christian D Zillikens, Detlef Schwaninger, Markus |
| AuthorAffiliation | 3 Department of Dermatology, Allergy, and Venereology, University of Lübeck , Lübeck , Germany 2 Department of Pharmacology, Max Planck Institute for Heart and Lung Research , Bad Nauheim , Germany 1 Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck , Lübeck , Germany |
| AuthorAffiliation_xml | – name: 3 Department of Dermatology, Allergy, and Venereology, University of Lübeck , Lübeck , Germany – name: 1 Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck , Lübeck , Germany – name: 2 Department of Pharmacology, Max Planck Institute for Heart and Lung Research , Bad Nauheim , Germany |
| Author_xml | – sequence: 1 givenname: Melanie surname: Wannick fullname: Wannick, Melanie organization: Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany – sequence: 2 givenname: Julian C surname: Assmann fullname: Assmann, Julian C organization: Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany – sequence: 3 givenname: Jakob F surname: Vielhauer fullname: Vielhauer, Jakob F organization: Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany – sequence: 4 givenname: Stefan surname: Offermanns fullname: Offermanns, Stefan organization: Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany – sequence: 5 givenname: Detlef surname: Zillikens fullname: Zillikens, Detlef organization: Department of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, Germany – sequence: 6 givenname: Christian D surname: Sadik fullname: Sadik, Christian D organization: Department of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, Germany – sequence: 7 givenname: Markus surname: Schwaninger fullname: Schwaninger, Markus organization: Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany |
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| CitedBy_id | crossref_primary_10_1016_j_jid_2020_06_028 crossref_primary_10_1111_dth_14376 crossref_primary_10_3389_fimmu_2020_01715 crossref_primary_10_1016_j_freeradbiomed_2021_03_040 crossref_primary_10_1016_j_mcn_2020_103493 crossref_primary_10_1016_j_jid_2021_01_014 crossref_primary_10_1016_j_det_2018_12_003 crossref_primary_10_1111_jdv_15816 crossref_primary_10_1111_bjd_19899 crossref_primary_10_1038_s41467_024_49536_y crossref_primary_10_2147_PTT_S417427 crossref_primary_10_1016_j_jid_2022_01_031 crossref_primary_10_3390_ph14010015 crossref_primary_10_1016_j_redox_2022_102299 crossref_primary_10_1016_j_jid_2021_04_009 crossref_primary_10_3389_fimmu_2023_1197709 |
| Cites_doi | 10.1111/exd.13415 10.1172/JCI72151 10.4049/jimmunol.1400401 10.1038/ncomms9726 10.1016/S0190-9622(94)70121-0 10.1084/jem.20072404 10.1038/JID.2015.361 10.2119/molmed.2015.00206 10.1016/j.jneuroim.2011.11.009 10.4049/jimmunol.1501604 10.4049/jimmunol.1400807 10.1016/S0140-6736(12)61140-4 10.1146/annurev.pharmtox.48.113006.094746 10.1038/ncomms13581 10.1002/path.2157 10.1016/j.bbrc.2008.08.041 10.1111/all.13376 10.1038/nm824 10.1007/s00441-017-2774-x 10.1126/science.aan4665 10.1038/sj.cdd.4402238 10.1016/j.jid.2016.12.021 10.1038/ncomms4944 10.1182/blood-2007-07-100610 10.1146/annurev-immunol-051116-052235 10.1016/S0065-7743(10)45005-8 10.1056/NEJMoa1114287 10.1093/brain/awq386 10.1172/JCI200521386 10.1016/j.tips.2017.11.002 10.1172/JCI42273 10.1038/srep38357 10.1146/annurev-immunol-051116-052215 |
| ContentType | Journal Article |
| Copyright | Copyright © 2018 Wannick, Assmann, Vielhauer, Offermanns, Zillikens, Sadik and Schwaninger. 2018 Wannick, Assmann, Vielhauer, Offermanns, Zillikens, Sadik and Schwaninger |
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| Keywords | G protein-coupled receptor pemphigoid disease immunomodulatory therapy autoimmune blistering skin disease neutrophils |
| Language | English |
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| Notes | 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 |
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| Snippet | 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... |
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| StartPage | 1890 |
| SubjectTerms | autoimmune blistering skin disease G protein-coupled receptor Immunology immunomodulatory therapy neutrophils pemphigoid disease |
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| Title | The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/30154797 https://search.proquest.com/docview/2096555546 https://pubmed.ncbi.nlm.nih.gov/PMC6102353 https://doaj.org/article/f177abcfd0504772a327881398512f95 |
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