A novel role of IL-17A in contributing to the impaired suppressive function of Tregs in psoriasis

Background: Regulatory T cells (Tregs) are crucial in maintaining T cell homeostasis and preventing autoimmune responses. Deficiencies in the suppressive function of Tregs contribute to the pathogenesis of various autoimmune diseases, such as psoriasis. However, whether IL-17A upregulation in psoriatic patients contributes to Treg dysfunction is unknown. Objective: To explore the effect and underlying mechanism of IL-17A on the suppressive function of Tregs and to evaluate the restoration of the suppressive function of Tregs in psoriasis during anti-IL-17A (secukinumab) treatment. Methods: In vitro suppression assays were performed with or without the addition of IL-17A to the coculture system. The release of inhibitory cytokines, including IL-10 and TGF-beta, was assessed by qRT-PCR and flow cytometry. RNA-sequencing was conducted to characterize the cellular responses of Tregs. IL-17A signaling activation was analyzed by flow cytometry and immunofluorescence. Blood samples were collected from three psoriasis patients before and after secukinumab treatment. Results: IL-17A blocked the suppressive function of Tregs, possibly by inhibiting the release of TGF-beta and promoting the production of IFN-gamma. Moreover, IL-17A activated the NF-kappa B signaling pathway in Tregs. Inhibition of the NF-kappa B pathway blocked IL-17A-induced upregulation of IFN-gamma without affecting the secretion of TGF-beta by Tregs. Clinical treatment in psoriasis with secukinumab restored the suppressive function and increased production of TGF-beta in Tregs of psoriasis. Conclusion: Our study implies a crucial role of IL-17A in mediating the dysfunction of the Treg suppressive function in psoriasis. Secukinumab, which neutralizes IL-17A signaling, restored the suppressive function of Tregs to exert its antipsoriatic effect. (C) 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

Automated summary

IL-17A inhibits the suppressive function of Tregs by blocking TGF-beta release and promoting IFN-gamma production. Treatment with anti-IL-17A in psoriasis patients restores the suppressive function of Tregs.