Abstract
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-1β). Inflammation dampens reverse cholesterol transport (RCT) and promotes atherogenesis, while anti-IL-1β antibodies were shown to reduce cardiovascular disease in humans. Though Nlrp3/IL-1β 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-1β 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-1β 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.
Summary GsdmD mediates inflammation induced defects in RCT and promotes atherosclerosis
Competing Interest Statement
The authors have declared no competing interest.
Non-standard abbreviations and acronyms
- ASO
- antisense oligonucleotides
- CAD
- Coronary artery disease
- CANTOS
- Canakinumab Anti-Inflammatory Thrombosis Outcomes Study
- GsdmD
- Gasdermin D
- IL-1β
- Interleukin 1-beta
- IL-18
- Interleukin 18
- LDLr
- Low-density lipoprotein receptor
- MACE
- Major adverse coronary events
- NLRP3
- NOD-like receptor family pyrin domain-containing 3
- NETs
- Neutrophil extracellular traps
- PIP2
- phosphatidylinositol 4,5-bisphosphate
- PS
- phosphatidylserine
- TLR
- toll like receptor