Psoriasis TNF-α therapeutic effects mediated by MSC antioxidant reduction

By Ingrid Grasmo

The therapeutic effects of tumor necrosis factor (TNF)-α inhibitors in psoriasis occur through a reduction in the antioxidant response of mesenchymal stem cells (MSCs), suggest study findings.

"Anti-TNF-α therapies might interfere with the 'psoriatic march' at a very early stage by acting on MSCs," say Roberto Di Primio (Universita Politecnica delle Marche, Ancona, Italy) and colleagues.

In psoriasis, several Th1 cytokines, vascular endothelial growth factor (VEGF), and nitric oxide (NO) are directly implicated in initiation, maintenance, and recurrence of skin lesions.

The effect of TNF-α inhibitors on differentiated skin cells has already been demonstrated in psoriasis, but no data have been reported on their effect on MSCs.

For the study, Di Primio and team performed biochemical, morphological, and immunohistochemical analyses in MSCs isolated from non-lesional, peri-lesional, and lesional skin of patients with psoriasis, before and after 12 weeks of treatment with adalimumab or etanercept.

The researchers found that 12-week treatment with the TNF-α inhibitors significantly reduced immunohistochemical expression and production of VEGF and NO in MSCs from psoriatic skin samples.

"This is an intriguing aspect, as the more effective systemic therapies currently established for the treatment of psoriasis do not only modulate the immune response of disease, but also directly inhibit angiogenesis," say the researchers.

In addition, the percentage of MSCs expressing inducible NO synthetase (iNOS) decreased in non-lesional psoriatic skin, with etanercept also reducing iNOS-positive MSCs in perilesional and lesional areas.

Adalimumab and etanercept were found to differentially influence the antioxidant response of MSCs, according to the area of skin biopsy, with MSCs obtained from lesional skin appearing the least sensitive to anti-TNF-α treatments.

Furthermore, both treatments induced superoxide dismutase activity in MSCs resident in lesional and perilesional skin, suggesting that "induction of this antioxidant enzyme is one of the most important benefits due to treatment with the TNF-α inhibitors," according to the authors.

Indeed, a general inhibition of glutathione S-transferase and catalase was observed in response to treatment, with these effects supported by a general decrease of total oxyradical scavenging capacity towards hydroxyl radicals and peroxynitrite.

Writing in the British Journal of Dermatology, the researchers say the findings suggest that anti-TNF-α treatment rebalances the strong pro-oxidant pressure exerted by the release of reactive oxygen species in inflamed tissues during the acute phase of the disease.

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