GBP5 Inhibition Ameliorates the Progression of Lupus Nephritis by Suppressing NLRP3 Inflammasome Activation

Abstract

ABSTRACT Background The inflammatory response and NLRP3 inflammasome activation are typical characteristics of lupus nephritis (LN). Guanylate-binding protein 5 (GBP5) has effects on the release of proinflammatory cytokines and the activation of NLRP3 inflammasome. However, it is largely unknown whether and how GBP5 contributes to the progression of LN. Methods To detect the role of GBP5 in LN, MRL/lpr mice were administrated with the lentiviral vectors that knockdown GBP5 via tail vein. Proximal tubular epithelial HK-2 cells were treated with LPS and ATP to mimic the inflammatory response of LN in vitro. Results GBP5 expression was increased in the renal cortical tissues of LN mice. The in vivo results showed that GBP5 inhibition prevented the progression of LN, as evidenced by the decreased levels of 24-hour proteinuria, blood urea nitrogen and creatinine, accompanied by the ameliorated renal pathological damages. The increased mRNA and protein levels of proinflammatory factors (IL-6, TNF-α, iNOS and COX-2) in the renal cortex of LN mice were suppressed by GBP5 knockdown. In vitro, we demonstrated that the treatment of LPS combined with ATP induced an increase in GBP5 mRNA and protein expression in HK-2 cells. Mechanically, knockdown of GBP5 inhibited the activation of NLRP3 inflammasome and the secretion of IL-1β and IL-18 both in vivo and in vitro. Conclusion Our findings reveal that GBP5 inhibition prevents the progression of LN, most likely by suppressing NLRP3 inflammasome activation. It provides a novel insight into the therapeutic interventions for LN.