Dimethyl fumarate modulates neutrophil extracellular trap formation in a glutathione and superoxide-dependent manner

Abstract

Background

Neutrophil (polymorphonuclear) granulocytes (PMN) were shown to contribute to the pathogenesis of psoriasis by releasing IL-17 and LL-37/ DNA complexes via neutrophil extracellular traps (NET), webs of chromatin strands decorated with antimicrobial peptides, in psoriatic skin. Fumaderm^®, a fumaric acid ester (FAE) formulation consisting of different FAE salts has been successfully used to treat psoriasis for decades. Most recently, FAE treatment was reported to inhibit NET formation in murine epidermolysis bullosa acquisita.

Objective

To elucidate the effect of FAE treatment on human psoriasis and healthy donor NET formation.

Results

Among the compounds present in the FAE formulation, dimethyl fumarate (DMF) pre-treatment of human psoriasis and healthy donor PMN resulted in a consistent inhibitory effect on NET formation to phorbol 12-myristate 13-acetate (PMA), but not to platelet activating factor and ionomycin. This effect was L-Glutathione dependent and involved the reduction of reactive oxygen species (ROS) production, a key event in NET formation. In contrast, G protein-coupled signaling and protein synthesis were not involved. Monomethyl fumarate (MMF) was found to slightly reduce ROS production without affecting NET formation.

Conclusions

We report DMF as a potent, stimulus-specific, L-Glutathione, and ROS-dependent modulator of NET formation. Our results support the notion that modulation of NET formation contributes to the beneficial effects of fumaric acid esters in a variety of inflammatory conditions.

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