Gasdermin D Mediates Inflammation-Induced Defects In Reverse Cholesterol Transport And Promotes Atherosclerosis

Activation of inflammasomes, such as Nlrp3 and AIM2, can exacerbate atherosclerosis in mice and humans. Gasdermin D (GsdmD) serves as a final executor of inflammasome activity, by generating membrane pores for the release of mature Interleukin-1beta (IL-1 beta). Inflammation dampens reverse cholesterol transport (RCT) and promotes atherogenesis, while anti-IL-1 beta antibodies were shown to reduce cardiovascular disease in humans. Though Nlrp3/AIM2 and IL-1 beta nexus is an emerging atherogenic pathway, the direct role of GsdmD in atherosclerosis is not yet fully clear. Here, we used in vivo Nlrp3 inflammasome activation to show that the GsdmD(-/-) mice release similar to 80% less IL-1 beta vs. Wild type (WT) mice. The GsdmD(-/-) macrophages were more resistant to Nlrp3 inflammasome mediated reduction in cholesterol efflux, showing similar to 26% decrease vs. similar to 60% reduction in WT macrophages. GsdmD expression in macrophages exacerbated foam cell formation in an IL-1 beta dependent fashion. The GsdmD(-/-) mice were resistant to Nlrp3 inflammasome mediated defect in RCT, with similar to 32% reduction in plasma RCT vs. similar to 57% reduction in WT mice, similar to 17% reduction in RCT to liver vs. 42% in WT mice, and similar to 37% decrease in RCT to feces vs. similar to 61% in WT mice. The LDLr antisense oligonucleotides (ASO) induced hyperlipidemic mouse model showed the role of GsdmD in promoting atherosclerosis. The GsdmD(-/-) mice exhibit similar to 42% decreased atherosclerotic lesion area in females and similar to 33% decreased lesion area in males vs. WT mice. The atherosclerotic plaque-bearing sections stained positive for the cleaved N-terminal fragment of GsdmD, indicating cleavage of GsdmD in atherosclerotic plaques. Our data show that GsdmD mediates inflammation-induced defects in RCT and promotes atherosclerosis.