Gasdermin D mediates inflammation-induced defects in reverse cholesterol transport and promotes atherosclerosis

Nlrp3 inflammasome is activated in advanced human atherosclerotic plaques. Gasdermin D (GsdmD) serves as a final executor of Nlrp3 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/IL-1{beta} nexus is an emerging atherogenic pathway, the direct role of GsdmD in atherosclerosis is not yet clear. Here, we used in-vivo Nlrp3 inflammasome activation to show that the GsdmD-/- mice release [~]80% less IL-1{beta} vs WT mice. The GsdmD-/- macrophages were more resistant to Nlrp3 inflammasome mediated reduction in cholesterol efflux, showing [~]26% decrease vs. [~]60% reduction in WT macrophages. GsdmD expression in macrophages exacerbated foam cell formation in an IL-1{beta} dependent fashion. The GsdmD-/- mice were resistance to Nlrp3 inflammasome mediated defect in RCT, with [~]32% reduction in plasma RCT vs. [~] 57% reduction in WT mice, [~] 17% reduction in RCT to liver vs. 42% in WT mice, and [~] 37% decrease in RCT to feces vs. [~] 61% in WT mice. The LDLr anti-sense oligonucleotides (ASO) induced hyperlipidemic mouse model showed role of GsdmD in promoting atherosclerosis. The GsdmD-/- mice exhibit [~]42% decreased atherosclerotic lesion area in females and [~]33% decreased lesion area in males vs. WT mice. The atherosclerotic plaque-bearing WT mice showed the presence of cleaved N-terminal fragment of GsdmD, indicating cleavage of GsdmD during atherosclerosis. Our data show that GsdmD mediates inflammation-induced defect in RCT and promotes atherosclerosis. SummaryGsdmD mediates inflammation induced defects in RCT and promotes atherosclerosis