Abstract 431: Nlrp3 Inflammasome Inhibits Cholesterol Efflux in Macrophages by Downregulating Gpr109a Expression. A Novel Proatherogenic Mechanism

Recent studies suggest that Nlrp3 inflammasome activation plays a critical role in the development of atherosclerosis and Chlamydia pneumoniae (Cpn ) infection has been shown to accelerate atherogenesis. Herein, we asked whether Cpn infection induced acceleration is via Nlrp3 inflammasome activation in hypercholestrolemia mouse model. Nlrp3 -/- Ldlr -/- , Casp1 -/- Ldlr -/- and Ldlr -/- mice were infected intranasally with Cpn followed by western diet (WD) for 16 weeks. Ldlr -/- mice infected with Cpn infection had markedly increased lesion size in the aortic sinus and aorta en face compared to WD only group. Casp1 activation in lesion macrophages in Ldlr -/- mice was also increased in Cpn group vs controls. Nlrp3 -/- Ldlr -/- or Casp1 -/- Ldlr -/- mice with and without Cpn resulted in significantly smaller of plaques in aortic root and aorta compare to Ldlr -/- mice. However, no difference was observed between Cpn infected and uninfected groups in the double knockout animals. Furthermore, foam cell formation of Nlrp3 -/- , and Casp1 -/- peritoneal macrophages after treatment with OxLDL and Cpn was significantly reduced when compared with WT cells. Interestingly, expression levels of the cholesterol efflux transporter, ATP-binding cassette A1 (ABCA1), was increased by RT PCR and western analysis in the KO macrophages. Further investigations found that the niacin receptor Gpr109a, a known positive regulator of ABCA1, was upregulated in Nlrp3 KO macrophages during foam cell formation. Hydroxy-butyrate, an activating ligand of GPR109, was produced by macrophages after Cpn infection indicating a feedback loop. Intact IL-1 signaling suppressed Gpr109a expression suggesting a pathway by which the inflammasome and IL-1β could enhance foam cell formation. In aortic root lesions, macrophage expression of Gpr109a was increased in Nlrp3 -/- Ldlr - - mice compare with Ldlr -/- mice on WD and infected with Cpn . In conclusion, the activation of the NLRP3 inflammasome negatively regulate Gpr109a receptor and its downstream cholesterol efflux transporter ABCA1, which leads to more foam cell formation and acceleration of atherosclerosis in Ldlr -/- mice. This work was supported by the National Institutes of Health grant HL111483 (to S. Chen)