Blocking cGAS/STING signaling protects against sepsis-associated acute liver injury

Abstract

Sepsis-associated acute liver injury (ALI) contributes to the pathogenesis of multiple organ dysfunction syndrome and thus increases mortality. Nevertheless, specific therapeutics for sepsis-associated ALI are scant so far. The cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, is implicated in a series of inflammatory diseases. However, whether cGAS functions in the pathogenesis of ALI is still unclear. We herein investigated the role of cGAS in the development of ALI, and if any, by which mechanism cGAS is involved. After a challenge using cecum ligation and puncture (CLP) or lipopolysaccharide (LPS) plus d-galactosamine (GalN) in WT and gene-modified mice, we found that cGAS signaling was activated, and cGAS deficiency significantly attenuated CLP- or LPS/GalN-induced liver injury, liver dysfunction and so-caused mice death. In addition, CLP or LPS/GalN augmented type I interferon signaling-the downstream of cGAS pathway. Recombinant interferon-β (rIFNβ) enhanced LPS/GalN-induced hepatocyte death and partly reversed the protection induced by cGAS depletion. Besides of inflammation, cGAS deletion was capable of preventing LPS/GalN-induced hepatocyte death. Hepatocyte-specific deletion of STING, the downstream of cGAS activation, showed a significant protection against ALI, which could be phenocopied by pharmacological inhibition of cGAS or STING via RU.521 or H-151 respectively. Taken together, cGAS/STING signaling promotes ALI by both type I IFN responses and hepatocyte death. Inhibition of cGAS/STING signaling would be a promising strategy for preventing ALI in sepsis.

Keywords: Interferons; STING; Sepsis, Acute liver injury; cGAS.