Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

Chad N. Brocker; Donghwan Kim; Tisha Melia; Kritika Karri; Thomas J. Velenosi; Shogo Takahashi; Jessica A. Bonzo; David J. Waxman; Frank J. Gonzalez

Pharmacological activation of PPARA deregulates NRLP3 inflammasome activity in a mouse model of diabetes (Deng et al., 2017) and prolonged hepatic NLRP3 inflammasome activation leads to hepatocyte death, inflammation, and fibrosis. Thus, the TXNIP-mediated NLRP3 inflammasome pathway was examined. Txnip mRNA was significantly decreased by PPARA activation in livers of wild-type, Gm15441 +/+ mice, while TXNIP protein was elevated in livers of Gm15441 LSL mice. Furthermore, TXNIP-mediated NLRP3 inflammasome activation resulted in cleavage of CASP1 to its mature, proteolytically active form. Mature CASP1 subsequently cleaves target proteins including the proinflammatory cytokine IL1B to its corresponding mature, active form. Mature, cleaved CASP1 and IL1B protein were elevated in Gm15441 LSL mice, indicating an increase in inflammasome activation. These findings indicate that lncRNA Gm15441 suppresses the TXNIP-mediated NLRP3 inflammasome pathway in response to metabolic stress.