First Author | Opoku E | Year | 2021 |
Journal | Front Cell Dev Biol | Volume | 9 |
Pages | 715211 | PubMed ID | 34395445 |
Mgi Jnum | J:334451 | Mgi Id | MGI:6817800 |
Doi | 10.3389/fcell.2021.715211 | Citation | Opoku E, et al. (2021) Gasdermin D Mediates Inflammation-Induced Defects in Reverse Cholesterol Transport and Promotes Atherosclerosis. Front Cell Dev Biol 9:715211 |
abstractText | 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-1beta). Inflammation dampens reverse cholesterol transport (RCT) and promotes atherogenesis, while anti-IL-1beta antibodies were shown to reduce cardiovascular disease in humans. Though Nlrp3/AIM2 and IL-1beta 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 approximately 80% less IL-1beta vs. Wild type (WT) mice. The GsdmD(-/-) macrophages were more resistant to Nlrp3 inflammasome mediated reduction in cholesterol efflux, showing approximately 26% decrease vs. approximately 60% reduction in WT macrophages. GsdmD expression in macrophages exacerbated foam cell formation in an IL-1beta dependent fashion. The GsdmD(-/-) mice were resistant to Nlrp3 inflammasome mediated defect in RCT, with approximately 32% reduction in plasma RCT vs. approximately 57% reduction in WT mice, approximately 17% reduction in RCT to liver vs. 42% in WT mice, and approximately 37% decrease in RCT to feces vs. approximately 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 approximately 42% decreased atherosclerotic lesion area in females and approximately 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. |