STING Drives Psoriatic Inflammation by Promoting Neutrophil Recruitment and Facilitating NETosis

Area of Science:

• Immunology
• Dermatology
• Molecular Biology

Background:

• Psoriasis is a chronic inflammatory disease where neutrophils play a key role.
• The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway's involvement in neutrophil-mediated psoriasis pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the role of the STING pathway in neutrophil function and inflammation in psoriasis.
• To explore STING's impact on neutrophil recruitment, cytokine secretion, and NET formation.

Main Methods:

• Single-cell RNA sequencing of human psoriatic lesions.
• Studies using imiquimod (IMQ)-induced mouse models (wild-type, STING-/-, PADi4-/-) and HL-60 cells.
• Transcriptomic, cytometric, and functional assays to analyze neutrophil behavior.

Main Results:

• STING expression is upregulated in neutrophils of psoriasis patients.
• STING knockout in mice reduced psoriasis severity, neutrophil infiltration, and IL-1β release.
• STING signaling promotes neutrophil migration via IRF3/NF-κB and directly regulates NET formation and cytotoxic mediator release.

Conclusions:

• STING signaling in neutrophils is a key driver of psoriatic inflammation, regulating both cell recruitment and NET production.
• Genetic heterogeneity in STING pathway activation suggests complex, context-dependent regulation and potential for individualized therapies.
• Targeting the STING pathway presents a promising therapeutic strategy for psoriasis by inhibiting multiple neutrophil-driven pathogenic processes.