CircELK4 Contributes to Lupus Nephritis by Acting as a miR-27b-3p Sponge to Regulate STING/IRF3/IFN-I Signaling

Abstract

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease and a common complication of SLE is lupus nephritis (LN) during which lupus autoantibodies and proinflammatory cytokines attack the kidney and cause renal dysfunction. The current treatments to LN are limited due to a poor understanding of the pathogenesis. Here, we studied the molecular mechanisms of LN by investigating the function of circELK4/miR-27b-3p axis. MRL/lpr mice and LPS-treated HK-2 cells were used as the mouse model and cell model of LN, respectively. Blood samples were collected from LN patients. qRT-PCR and western blot were used to measure expression levels of circELK4, miR-27b-3p, apoptosis-related proteins, cytokines, and STING/IRF-3/IFN-I signaling. ELISA was performed to examine levels of cytokines including IL-6 and TNF-α. H&E staining was used to examine kidney morphology. TUNEL staining and flow cytometry were used to determine cell apoptosis. Dual luciferase activity assay and RNA pull down were employed to validate the interactions of circELK4/miR-27b-3p and miR-27b-3p/STING. CircELK4 was elevated in LN mice, patients, and LPS-treated HK-2 cells. Knockdown of circELK4 attenuated renal injury in LN mice and LPS-induced HK-2 cell injury. CircELK4 directly bound to miR-27b-3p while miR-27b-3p targeted STING. Moreover, overexpression of circELK4 could partially reverse the effects of miR-27b-3p mimics on cell apoptosis and inflammation. Furthermore, circELK4/miR-27b-3p regulated renal cell damage via modulating STING/IRF3/IFN-I signaling. CircELK4 contributes to renal injury by promoting inflammation and cell apoptosis via acting as a miR-27b-3p sponge to modulate STING/IRF3/IFN-I signaling in LN.

Keywords: STING/IRF3/IFN-I signaling; circELK4; lupus nephritis; miR-27b-3p.