Abstract 15577: The Activation of Nlrp3 Inflammasome Mediates Diet- and Chlamydia Pneumonia- Induced Acceleration of Atherosclerosis by Th17 Skewing
Background: The role of Nlrp3 inflammasome activation in the development of atherosclerosis in hypercholesterolemic mice is still controversial, and its role in Chlamydia pneumonia (Cp) infection accelerated atherosclerosis is also unclear.
Objective: We investigated the role of the Nlrp3 inflammasome in high-fat diet (HFD) and Cp induced acceleration of atherosclerosis and its potential mechanism.
Methods and Results: We created 3 groups of Bone Marrow chimeric (BMC) mice (Donor → Recipient): WT →Ldlr-/- ; Nlrp3-/- → Ldlr-/- ; Casp1-/- → Ldlr-/-. After 16 wks HFD, quantification of the lesion area of aortic sinus plaques and lipid content revealed a significant reduction in lesion size and lipid content in the aortic root and in aorta en face in Nlrp3-/- (25%, 32%, 25%), and Casp1-/- (26%, 32%, 26%) BMC compared to WT BMC mice, despite similar cholesterol levels. In next experiments, mice were infected with Cp or vehicle once a week for 3 wks and fed HFD for 16 wks before sacrificing. Nlrp3-/- and Casp1-/- BMCs resulted in a 28% and 35% decrease in the size and lipid content of lesions in the aortic sinus and a 25% decrease in aorta en face lesion coverage in Cp plus HFD groups. However, Cp infection still led to a significant increase (40%) in size and lipid content of the atherosclerotic lesions in WT BMC, as well as the Nlrp3-/-, and Casp1-/- BMCs compared to non-infected counterparts. We next investigated the mechanism of the athero-protection that we have seen in Nlrp3-/- BMC by generating Ldlr-/-/Nlrp3-/- double knockout mice (DKO). After 16 wks HFD, compared with Ldlr-/- mice, the aortic sinus lesion size, lipid composition, and aortic en face lesion coverage in the lesions in the DKO mice were diminished by 33%, 40%, and 37% respectively. Despite similar levels of total plasma cholesterol, MCP-1 was decreased while IL-10 levels were increased in plasma of DKO mice compared to Ldlr-/- mice. Flow cytometry of stimulated splenocytes revealed a significant reduction in the percentage of CD4+ IL-17A and F producing cells in Nlrp3-/- and Casp1-/- BMC compared to WT BMC as well as in DKO compared to Ldlr-/- mice.
Conclusion: Our data suggest that the Nlrp3 inflammasome plays an important role in both diet- and Cp infection-mediated atherosclerosis, likely through TH17 skewing.
Author Disclosures: G. Tumurkhuu: None. W. Zhang: None. K. Shimada: None. G. Huang: None. T. Crother: None. M. Arditi: None. S. Chen: None.
- © 2014 by American Heart Association, Inc.