HCA2 Activation in Pemphigoid Diseases - Therapeutic Effects and Mode of Action

The drug dimethyl fumarate (DMF) has been used for several decades to treat psoriasis and has been licensed as first-line therapy in the treatment of multiple sclerosis. In both diseases, the mode of action, however, has been elusive. The Department of Experimental and Clinical Pharmacology of the UzL has recently provided evidence that DMF ameliorates multiple sclerosis by compromising neutrophil recruitment into the CNS through agonism of its active metabolite monomethyl fumarate (MMF) at the hydroxyl-carboxylic acid receptor 2 (HCA2/GPR109A). β-hydroxybutyrate, butyrate, and nicotinic acid (niacin) are endogenous ligands of HCA2. Its physiological significance is not entirely clear, but a certain level of HCA2 activation has been shown to be continuously required to maintain tissue homeostasis in the gut mucosa suggesting that this receptor participates in setting the threshold for the emergence of tissue inflammation. In line with this notion, reduced activity of HCA2 is also thought to promote Parkinson’s disease. Interestingly, there is an increased co-incidence of Parkinson’s disease with bullous pemphigoid. In parallel, the Department of Dermatology of the UzL has recently found that DMF also significantly ameliorates PD skin inflammation in the AAb transfer EBA mouse model. The mode of action of DMF in this model, however, has remained elusive. Therefore, the pharmacological rationale for the use of DMF in the treatment of PD, which would largely facilitate its introduction into clinical use in PD, is still missing. Project 8 will therefore set out to elucidate the mode of action of DMF in PD skin inflammation. Herein, it will particularly focus on HCA2 and will also investigate the impact endogenous HCA2 ligands may exert to modulate the course of skin inflammation.