411 CO-releasing fumarate complexes show superior anti-inflammatory effects compared to dimethyl fumarate treatment

Abstract

Inflammatory autoimmune diseases like psoriasis and multiple sclerosis are characterized by the aberrant induction of interleukin (IL-) 12 and IL-23-producing type I dendritic cells (DC), resulting in pathogenic Th1/Th17 cell responses. We previously showed that the small molecule dimethyl fumarate (DMF) is able to improve inflammatory diseases by exerting potent immune modulatory activities. DMF treatment results in the generation of type II dendritic cells (DC) which then induce an anti-inflammatory Th2 response. In addition, carbon monoxide (CO) is an emerging therapeutic agent for various conditions characterized by a hyperactivated immune system. We therefore reasoned to chemically combine fumaric acid and CO in a single molecule and synthesized CO-releasing molecules linked to methyl fumarate (FumET-CORMs). Treatment of bone marrow derived dendritic cells (BMDC) with FumET-CORMs substantially increased ROS levels in a fashion similar to DMF treatment alone. In addition, we analyzed the effects on the HO-1 and STAT1 signaling pathways by Western Blot analysis and ELISA. These experiments revealed that treatment with FumET-CORMs resulted in the induction of HO-1 and inhibited STAT1 phosphorylation. This subsequently led to reduced IL-23 and IL-12 levels in culture supernatants. FumET-CORMs exhibited a substantially improved anti-inflammatory activity as compared to the clinically used drug DMF. Importantly, the inhibitory effects on HO-1 and STAT1 signaling were stronger and occurred at lower concentrations. Therefore, our data confirm the concept that combining fumaric acid with CO-releasing molecules is a highly effective therapeutic option by transforming proinflammatory dendritic cells into a type II phenotype. In summary, FumET-CORMs have great potential, e.g. for the treatment of psoriasis or other inflammatory conditions of the skin.