STING Drives Psoriatic Inflammation by Promoting Neutrophil Recruitment and Facilitating NETosis

Psoriasis is a chronic, immune-mediated inflammatory disorder in which neutrophils are central to pathogenesis. While recent studies have implicated the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway in psoriasis, its specific role in neutrophil-mediated inflammation remains unclear. To investigate neutrophil function in psoriasis, we integrated single-cell RNA-seq from human lesions with studies in IMQ-treated mouse models (wild-type, STING-/-, PADi4-/-) and HL-60 cells. We employed transcriptomic, cytometric and functional assays to assess neutrophil recruitment, cytokine secretion and neutrophil extracellular trap (NET) formation. Our study revealed significant upregulation of STING expression in both lesional and peripheral blood neutrophils of psoriasis patients. In the IMQ-induced mouse model, STING knockout markedly alleviated disease severity, reduced neutrophil infiltration and suppressed IL-1β release. Mechanistically, STING promoted neutrophil chemotactic migration via the IRF3/NF-κB axis while directly regulating the formation of NETs in neutrophils and the release of cytotoxic mediators. Besides, distinct mouse strains exhibited significant differences in STING pathway activation, indicating genetic heterogeneity in the immunoregulatory mechanisms underlying psoriasis. Collectively, the above findings indicated that STING signalling in neutrophil-mediated psoriatic inflammation not only regulates cell recruitment but also directly drives the terminal effector function of NETs production. Furthermore, strain-specific differences suggest that the regulation of this pathway in the disease context is complex and context-dependent, potentially influencing individualised therapeutic responses. Targeting the STING pathway could serve as a therapeutic strategy to simultaneously inhibit multiple pathogenic processes mediated by neutrophils.