Dimethyl fumarate modulates the Treg–Th17 cell axis in patients with psoriasis*

Abstract

Summary Background Dimethyl fumarate (DMF) is the active ingredient of Skilarence™ and Tecfidera™, which are used for the treatment of psoriasis and multiple sclerosis, respectively. Various immunomodulatory mechanisms of action have been identified for DMF; however, it is still unclear what effects DMF exerts in vivo in patients with psoriasis. Objectives In this study we examined the effects of DMF, both in vivo and in vitro, on T cells, which play a key role in the pathogenesis of psoriasis. Methods The frequency of T‐cell subsets was examined by flow cytometry in untreated patients with psoriasis or those treated with DMF. The effects of DMF in vitro on T‐cell survival, activation and proliferation, and cell‐surface thiols were assessed by flow cytometry. Results In patients with psoriasis treated with DMF we observed an increase in the frequency of T regulatory (Treg) cells and a decrease in T helper (Th)17 lineage cells and the associated cytokines interleukin‐17, interleukin‐22 and granulocyte–macrophage colony‐stimulating factor. T cells cultured in vitro with DMF exhibited reduced viability, and inhibition of activation and proliferation in response to stimulation due to the oxidative effects of DMF. However, the frequency of Treg cells increased in the presence of DMF due to their heightened ability to resist DMF‐induced oxidative stress. Conclusions DMF enhanced the ratio of Treg cells to Th17 cells in patients with psoriasis, in patients with multiple sclerosis and in vitro. Furthermore, our data suggest that this is at least in part as a result of the differential effects of DMF on Treg cells compared with conventional T cells.

Dimethyl fumarate inhibits antibody-induced platelet destruction in immune thrombocytopenia mouse

“…Meanwhile, the level of Th1-associated IFN-γ and Treg-associated TGF-β1 also showed the consistent change with Th1 and Treg cells, further confirming the pathogenic role of Th1 and Treg cells in ITP development. Interestingly, after DMF treatment, Th1 cells were significantly reduced and Treg cells were increased along with downregualted T-bet/IFN-γ and upregulated Foxp3/TGF-β1 level, consistent with previous studies showing that DMF treatment significantly decreased Th1 subset and IFN- γ secretion in patients with multiple sclerosis [ 32 ] and induced an increase in the frequency of Treg cells in patients with psoriasis [ 33 ].…”

The Defect in Regulatory T Cells in Psoriasis and Therapeutic Approaches

“…DMF treatment increased Treg frequency and decreased Th17 cells in patients with psoriasis [61]. In vitro DMF treatment induced oxidative stress, which reduced the viability and proliferation of CD4 + CD25 − conventional T cells but did not reduce Tregs [62], by virtue of the increased expression of cell surface-reduced thiols [61] or thioredoxin-1 [63], protecting Tregs from oxidative stress. The oxidative effects of DMF may favor Tregs relative to Th17 cells, which may be another mechanism for the anti-psoriatic effects of DMF.…”

Mechanism of action of dimethyl fumarate: a small molecule with big effects

“…5 The work is relevant to our understanding of psoriasis, as the IL-17 family cytokines, in particular IL-17A, IL-17F and IL-17C, are overexpressed in psoriasis skin. 6 Blocking the IL-17 family of cytokines has a rapid clinical effect. However, it is still unknown whether blocking IL-17A alone (via ixekizumab or secukinumab), IL-17A and IL-17F (via bimekizumab), or IL-17A, IL-17C, IL-17 E and IL-17F (via brodalumab) is optimal.…”

“…Previous studies, both in multiple sclerosis and psoriasis, have shown a beneficial effect of DMF on interleukin-17 production. 6,7 DMF can induce changes in Langerhans cell function and can reduce inflammation by inhibition of NF-jB. 8 DMF has also been shown to inhibit glyceraldehyde 3-phosphate dehydrogenase, which affects immune function via so-called immunometabolic effects.…”