Regulation of proton‐coupled folate transporter in retinal Müller cells by the antipsoriatic drug monomethylfumarate

Abstract

Fumaric acid esters are used to treat psoriasis, an inflammatory skin disease characterized by keratinocyte proliferation. Inflammation and proliferation are hallmarks of retinal disease; hence, fumaric acid esters may have therapeutic value in retinal pathology. In diseased retinas, Müller glial cells (MCs) undergo reactive gliosis, a hyperproliferative state. MCs take up folate, a vitamin necessary for cell proliferation, via the proton-coupled folate transporter (PCFT). Here we examined the effect of monomethylfumarate (MMF), the active metabolite of fumaric acid esters, on expression and function of PCFT in MCs. Primary MCs, isolated from neonatal mouse retinas, were treated with MMF, and PCFT function was monitored by measuring uptake of radiolabeled methyltetrahydrofolate (MTF) at pH 5.5. Dose-response and time-course analyses were performed to identify optimal conditions for maximal effect. The influence of MMF treatment on kinetic parameters of PCFT was studied, and PCFT expression was analyzed at the mRNA and protein level. MTF uptake in MCs decreased by ~50% following 18 h treatment with 1 mM MMF. This effect was specific to fumaric acid esters. MMF treatment decreased the maximal velocity of the transporter without altering substrate affinity. The decrease in PCFT function following MMF treatment was accompanied by attenuated PCFT expression. This is the first report that an antipsoriatic compound can regulate folate transport in MCs and may have potential for the treatment of reactive gliosis in retinal disease.

Induction of the Cystine/Glutamate Exchanger SLC7A11 in Retinal Pigment Epithelial Cells by the Antipsoriatic Drug Monomethylfumarate

“…However, recent studies report potential benefits in other cell types, [5][6][7] leading to speculation that FAE therapy can be extrapolated to treatment of additional diseases, particularly those in which oxidant-induced cellular damage is majorly involved. This is directly relevant to retina, a tissue in which oxidative stress wreaks havoc.…”

The Antipsoriatic Agent Monomethylfumarate Has Antiproliferative, Prodifferentiative, and Anti-Inflammatory Effects on Keratinocytes

“…Furthermore, according to previous clinical and experimental studies, most of the DMF is hydrolyzed to MMF, which, in turn, is thought to act as an antipsoriatic agent (Rostami Yazdi and Mrowietz, 2008;Rostami-Yazdi et al, 2009). Therefore, in our study, we focused on the bioactive ingredient of the drug MMF, rather than the main ingredient, an apparent prodrug with low bioavailability, using MMF concentrations that have recently been examined in other cell types (Bozard et al, 2012;Ananth et al, 2013;Promsote et al, 2014).…”

Cystathionine Beta Synthase Expression in Mouse Retina

“…Breeding pairs of cbs +/− mice (B6.129P2-Cbs tm1Unc /J) were used to generate cbs −/− and cbs +/+ mice per our earlier reports [11, 12]. Three retinal cell types were isolated from wildtype (C57BL/6) mice: ganglion cells were isolated from mice at 3–4 days [13]; Müller glial cells at 5–7 days [14]; pigmented epithelial (RPE) cells at 3 weeks [15]. The purity of each of these primary cell types has been confirmed in previous studies.…”