In lupus nephritis, how do extracellular DNAs trigger type I interferon secretion: Under the assistance of HMGB1-cGAS?

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple organs involved. Kidney damage is common among SLE patients. In lupus nephritis, extracellular DNA accumulation from necrosis cells and activated cells is perceived as initial step of inflammation. The up-regulated type I IFN is one pivotal cytokine causing downstream inflammation enlargement. Currently, intracellular DNA sensor cGAS signaling has been found to be related to lupus nephritis and the aberrant up-regulation of type I IFN. However, how extracellular accumulated DNA activates intracellular cGAS is still unknown. It was reported that nuclear protein HMGB1 takes part in multiple autoimmune diseases and inflammation induction. When HMGB1 is secreted to extracellular environment under certain conditions, it combines with DNA and triggers IFN-I secretion. It has been reported that HMGB1 level in renal tissue and cGAS level in peripheral blood mononuclear cells were both significantly up-regulated in SLE patients. Hence, we present a hypothesis that in lupus nephritis, the released HMGB1 helps extracellular accumulated DNA endocytosis and cGAS signaling pathway activation, followed by IFN-I secretion. We infer this is one pivotal pro-inflammation pathway in lupus nephritis progression.