British journal of pharmacology · 2021
The STING antagonist H-151 ameliorates psoriasis via suppression of STING/NF-κB-mediated inflammation.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Pan Yanhong, You Yanping, Sun Li, Sui Qibang, Liu Liu, Yuan Haoliang, Chen Caiping, Liu Jun, Wen Xiaoan, Dai Liang, Sun Hongbin
Аннотация
BACKGROUND AND PURPOSE: Psoriasis is a chronic inflammatory skin disease associated with both innate and adaptive immune responses. The stimulator of interferon genes (STING) protein engages in sensing of cytosolic DNA to initiate dsDNA-driven immune responses. In vitro and in vivo anti-psoriasis effects of STING antagonist H-151 were explored.
EXPERIMENTAL APPROACH: We analysed the gene expression profile of STING and related downstream targets in the skin samples of healthy people and psoriasis patients from the GEO database. Cellular inhibitory activity of H-151 on STING pathway was confirmed via qPCR and western blotting. The preventive effect of topical application of H-151 on imiquimod-induced psoriatic mice was examined through histological, immunohistochemical, immunofluorescent, flow cytometric analysis, ELISA Kits and other approaches. Preliminary mechanistic studies were also performed.
KEY RESULTS: Gene expressions of STING and its downstream target were up-regulated in lesional skin samples from psoriasis patients. Topical administration of H-151 attenuated the skin lesions in imiquimod-induced psoriatic mouse model, while the secretion of pro-inflammatory cytokines (IL-17, IL-23 and IL-6), infiltration of M1 macrophages and differentiation of Th17 cells were significantly suppressed by H-151 treatment. Mechanistically, H-151 inhibited STING/NF-κB signalling in both keratinocytes and immune cells.
CONCLUSION AND IMPLICATIONS: H-151 displayed anti-inflammatory activity in both keratinocytes and immune cells, and decreased the severity of psoriatic response in vivo. Inhibition of STING signalling pathway may represent a novel therapeutic approach to psoriasis and related complications.
EXPERIMENTAL APPROACH: We analysed the gene expression profile of STING and related downstream targets in the skin samples of healthy people and psoriasis patients from the GEO database. Cellular inhibitory activity of H-151 on STING pathway was confirmed via qPCR and western blotting. The preventive effect of topical application of H-151 on imiquimod-induced psoriatic mice was examined through histological, immunohistochemical, immunofluorescent, flow cytometric analysis, ELISA Kits and other approaches. Preliminary mechanistic studies were also performed.
KEY RESULTS: Gene expressions of STING and its downstream target were up-regulated in lesional skin samples from psoriasis patients. Topical administration of H-151 attenuated the skin lesions in imiquimod-induced psoriatic mouse model, while the secretion of pro-inflammatory cytokines (IL-17, IL-23 and IL-6), infiltration of M1 macrophages and differentiation of Th17 cells were significantly suppressed by H-151 treatment. Mechanistically, H-151 inhibited STING/NF-κB signalling in both keratinocytes and immune cells.
CONCLUSION AND IMPLICATIONS: H-151 displayed anti-inflammatory activity in both keratinocytes and immune cells, and decreased the severity of psoriatic response in vivo. Inhibition of STING signalling pathway may represent a novel therapeutic approach to psoriasis and related complications.