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 pathway is an evolutionary conserved pathway for sensing and responding to DNA either pathogen-associated or endogenous DNA. DNA is sensed by cGAS and this enzymatically generates the second messenger cGAMP to bind the endoplasmic reticulum located STING that activates IRF-3 leading to expression of type I interferons. This pathway is necessary for viral infection response and anti-tumoral responses. Various autoinflammatory cutaneous diseases such 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 disease. In recent years key in vitro, ex vivo and in vivo evidence has been provided highlighting a crucial role of STING in both diseases and proving a rationale for therapeutic targeting. This review focussed primarily on the role of the pathway in SLE and SSc and provides a rationale for targeting the cGAS-STING pathway and suggests novel ways of augmenting this critical pathway.