#984 Macrophage BRCC3 ameliorates sepsis-induced kidney injury by mediating renal NLRP3 inflammation

Abstract

Abstract Background and Aims Sepsis-induced kidney injury (S-AKI) is an inflammatory disease characterized by high mortality rates. Macrophages are key inflammatory cells in the pathogenesis of S-AKI, and a rationale to target macrophage-endothelial cell interactions has been elucidated. Some study reported that BRCC3, a deubiquitylating enzyme, which is a critical regulator of NLRP3 activity in vitro experiments. However, the role of Macrophage BRCC3 role in S-AKI remains unclear. Method The S-AKI model was established by injecting lipopolysaccharide (LPS) into wild-type (WT) and macrophage-specific BRCC3 knockdown (KO-Mφ) mice. Transfecting RAW264.7 macrophages with siBRCC3 and establishing the co-culture system of RAW264.7 macrophages and murine tubular epithelial cells (mTECs) in Transwell. Results We found that macrophage BRCC3 deficiency ameliorates S-AKI. Compared with WT-S-AKI mice, the macrophage infiltration was decreased, the serum creatinine, BUN and the renal histologic injury scoring was decreased, as well as the expression of NLRP3 and Pro-Caspase-1 was clearly attenuated in KO-Mφ S-AKI mice. However, the serum IL-1β, IL-6, and TNF-α changes had on different between S-AKI groups. In vitro study, knockdown of BRCC3 in macrophages decreased NLRP3 inflammasome activation and cell apoptosis in mTECs. Mechanistically, BRCC3 knockdown promoted K63-linked ubiquitination of NLRP3 in macrophages. NLRP3 overexpression in mTEC abolished the renal protective effects of macrophages BRCC3 knockoff in S-AKI mice. Conclusion We showed that the macrophage BRCC3 as a key regulator in the activation of NLRP3 inflammasome by ubiquitination pathway in S-AKI. Our study unveils that macrophage BRCC3 has the potential to be the novel therapeutic target for S-AKI treatment.