Oral dimethyl fumarate induces changes within the peripheral neutrophil compartment of patients with psoriasis that are linked with skin improvement*

Abstract

Background: Dimethyl fumarate (DMF) is a treatment for moderate-to-severe psoriasis and multiple sclerosis. DMF therapy typically improves skin inflammation within the first 3 months of treatment. DMF is a prodrug that generates the hydroxycarboxylic acid receptor 2 (HCA2) agonist, monomethyl fumarate (MMF). Despite widespread clinical use, DMF’s mechanism of action is not fully understood. Objectives: We wished to characterize the changes induced by DMF in peripheral neutrophils within the first 3 months of treatment to better understand its early antipsoriatic effects. Methods: Flow cytometry was used to assess T-cell and neutrophil frequencies, apoptosis and activation phenotype. In vitro culture of neutrophils with DMF and MMF was used to evaluate apoptosis and HCA2 internalization. Serum levels of neutrophil degranulation products were measured by enzyme-linked immunosorbent assay. Results: Patients with psoriasis had significantly higher leucocyte counts at baseline compared with controls, with a large population of pro-inflammatory CD62Llo CD11bbright neutrophils. Analysis revealed that DMF treatment reduced the frequency of CD62Llo CD11bbright neutrophils and serum levels of neutrophil activation markers. This reduction was not linked to increased apoptosis. Conclusions: Our results reveal a novel in vivo effect of DMF therapy on pro-inflammatory neutrophils that likely contributes to this treatment’s antipsoriatic efficacy.