Dimethyl fumarate modulates neutrophil extracellular trap formation in a glutathione- and superoxide-dependent manner
J H O Hoffmann1, K Schaekel1, D Hartl2,3
1Department of Dermatology, University of Heidelberg, Heidelberg, Germany.
Background:
Neutrophil (polymorphonuclear) granulocytes (PMN) have been shown to contribute to the pathogenesis of psoriasis by releasing interleukin-17 and LL37-DNA complexes via neutrophil extracellular traps (NETs), 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.
Objectives:
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) pretreatment of human psoriasis and healthy donor PMN resulted in a consistent inhibitory effect on NET formation in response to phorbol 12-myristate 13-acetate but not to platelet activating factor and ionomycin. This effect was l-glutathione (GSH) dependent and involved a decrease in reactive oxygen species (ROS) production, a key event in NET formation. In contrast, G-protein-coupled signalling 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, GSH- and ROS-dependent modulator of NET formation. Our results support the notion that modulation of NET formation contributes to the beneficial effects of FAEs in a variety of inflammatory conditions.
Insights
Dimethyl fumarate (DMF) inhibits neutrophil extracellular trap (NET) formation in psoriasis by reducing reactive oxygen species (ROS). This finding supports fumaric acid esters (FAEs) as beneficial treatments for inflammatory conditions.
Area of Science:
- Immunology
- Dermatology
- Pharmacology
Background:
- Neutrophil extracellular traps (NETs) contribute to psoriasis pathogenesis.
- Fumaderm (FAE) is a long-standing psoriasis treatment.
- Previous studies suggest FAEs inhibit NET formation in other conditions.
Purpose of the Study:
- To investigate the effect of FAE treatment on NET formation in human psoriasis and healthy donors.
Main Methods:
- Pretreatment of neutrophils with dimethyl fumarate (DMF) and monomethyl fumarate (MMF).
- Stimulation of NET formation using phorbol 12-myristate 13-acetate, platelet activating factor, and ionomycin.
- Assessment of reactive oxygen species (ROS) production and l-glutathione (GSH) dependency.
Main Results:
- DMF consistently inhibited NET formation in response to phorbol 12-myristate 13-acetate.
- This inhibition was dependent on GSH and involved decreased ROS production.
- Monomethyl fumarate (MMF) showed minimal effect on NET formation.
Conclusions:
- Dimethyl fumarate (DMF) is a potent, stimulus-specific inhibitor of NET formation.
- The mechanism involves GSH and ROS reduction.
- Modulation of NET formation likely contributes to the therapeutic benefits of FAEs in inflammatory diseases.
