期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 178, 期 24, 页码 4907-4922出版社
WILEY
DOI: 10.1111/bph.15673
关键词
antagonist; IL-6; inflammation; NF-kappa B; psoriasis; STING
资金
- National Natural Science Foundation of China [81730094, 91853125, 81773584, 21977118]
- Jiangsu Natural Science Foundation [BK20202009]
STING and its downstream target genes were up-regulated in lesional skin samples from psoriasis patients. Topical application of H-151 inhibited skin lesions in a psoriatic mouse model, as well as the secretion of pro-inflammatory cytokines and activation of immune cells.
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-kappa B 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.
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