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

Melanie Wannick,Jakob F Vielhauer,Stefan Offermanns,Christian D Sadik,Markus Schwaninger,Detlef Zillikens,Julian C Assmann

doi:10.3389/fimmu.2018.01890

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 (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.

Highlights

Dimethyl fumarate (DMF) is an oral, immunomodulatory drug licensed for the treatment of multiple sclerosis (MS) and for moderate-to-severe plaque psoriasis
Oral DMF treatment reduced the number of infiltrating neutrophils in the spinal cord, and monomethyl fumarate (MMF) impaired the migration and adhesion of neutrophils in a hydroxycarboxylic acid receptor 2 (HCA2)-dependent manner, indicating that the therapeutic effect of DMF in MS may be partially due to an inhibition of neutrophil recruitment into the CNS
While DMF treatment had no significant effect on relative numbers of CD11b+Ly6CHi monocytes in the peripheral blood and of CD11b+Ly6CHi monocyte-derived cells in the skin, it reduced CD11b+Ly6CHi monocytes in the spleen and in lymph nodes by day 11 after the induction of epidermolysis bullosa acquisita (EBA) (Figures 2A,C; Figure S2 in Supplementary Material)

Summary

Introduction

Dimethyl fumarate (DMF) is an oral, immunomodulatory drug licensed for the treatment of multiple sclerosis (MS) and for moderate-to-severe plaque psoriasis. Oral DMF treatment reduced the number of infiltrating neutrophils in the spinal cord, and MMF impaired the migration and adhesion of neutrophils in a HCA2-dependent manner, indicating that the therapeutic effect of DMF in MS may be partially due to an inhibition of neutrophil recruitment into the CNS. The latter is a mechanism that has recently been suggested to be a key process in EAE and MS [8,9,10,11]. It belongs to the group of G protein-coupled receptors for short chain fatty acids, which have been uncovered to modify the course of disease of several autoimmune, autoinflammatory, and allergic diseases [13]

Methods

Results

Conclusion