Cytosolic DNA‒Mediated STING-Dependent Inflammation Contributes to the Progression of Psoriasis

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by an active dynamic interplay between immune cells and keratinocytes (KCs). STING is a universal receptor that recognizes cytosolic DNA and triggers innate immune activation. This study aims to elucidate the role of STING in the inflammation in psoriasis. STING deficiency alleviated psoriatic symptoms and inflammation in mouse models of psoriasis. Stimulation of macrophages with double-stranded DNA induced STING-dependent release of TNF-α and hydrogen peroxide in vitro. Furthermore, incubation of KCs with TNF-α or hydrogen peroxide increased oxidative DNA damage, induced nuclear DNA release into the cytosol, and inhibited double-stranded DNA‒induced degradation of STING protein. More importantly, transfection of KCs with double-stranded DNA synergized with TNF-α or hydrogen peroxide to induce STING-dependent activation of NF-κB and subsequent expression of Il1b, Ccl20, and Cxcl10. Finally, exposure to 5,6-dimethylxanthenone-4-acetic acid (a STING agonist) aggravated psoriatic symptoms and inflammation in wild-type mice but not in STING-deficient mice. Collectively, STING functioned as a self-DNA sensor in macrophages and KCs of psoriatic skin. Cytosolic DNA-induced activation of STING in immune cells and KCs acted synergistically and contributed to the inflammation in psoriasis.