Targeting the cGAS-STING pathway for therapeutic gain in autoimmune inflammatory cutaneous diseases with a focus on systemic lupus erythematosus and systemic sclerosis.

Abstract

The cGAS-STING [cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING)] pathway is an evolutionarily conserved pathway for sensing and responding to cytosolic double-stranded (ds)DNA, whether pathogen-associated or endogenous. Detection and binding of dsDNA by cGAS enzymatically generates the second messenger cGAMP, which in turn binds the endoplasmic reticulum-resident signalling protein STING, activating IRF3 (interferon regulatory factor 3), leading to expression of type I interferons. This pathway is necessary for both viral infection and antitumoral responses. Various autoinflammatory cutaneous diseases such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) also share key features, such as antibodies to nuclear fractions and a prominent type I interferon signature, suggesting that the cGAS-STING pathway may be important in these diseases. In recent years, key in vitro, ex vivo and in vivo evidence has been produced, highlighting a crucial role of STING in both diseases and providing a rationale for therapeutic targeting. This review focuses primarily on the role of the cGAS-STING pathway in SLE and SSc, emphasizing the rationale for therapeutic targeting and suggesting novel ways of augmenting this critical pathway.