Gasdermin D Mediates Inflammation-Induced Defects in Reverse Cholesterol Transport and Promotes Atherosclerosis.
Gasdermin D Mediates Inflammation-Induced Defects in Reverse Cholesterol Transport and Promotes Atherosclerosis.
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DOI：
10.3389/fcell.2021.715211
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发表时间：
2021
影响因子：
5.5
通讯作者：
Gulshan K
中科院分区：
文献类型：
--
作者：
Opoku E;Traughber CA;Zhang D;Iacano AJ;Khan M;Han J;Smith JD;Gulshan K
炎性体如Nlrp 3和AIM 2的激活可加剧小鼠和人类的动脉粥样硬化。Gasdermin D（GsdmD）通过产生用于释放成熟白细胞介素-1 β（IL-1β）的膜孔而充当炎性体活性的最终执行者。炎症抑制胆固醇逆向转运（RCT）并促进动脉粥样硬化形成，而抗IL-1β抗体显示可减少人类的心血管疾病。虽然Nlrp 3/AIM 2和IL-1β的关系是一个新出现的动脉粥样硬化的途径，但GsdmD在动脉粥样硬化中的直接作用尚不完全清楚。在此，我们使用体内Nlrp 3炎性小体活化来显示GsdmD-/-小鼠释放的IL-1β比野生型（WT）小鼠少80%。GsdmD-/-巨噬细胞对Nlrp 3炎性体介导的胆固醇流出减少更具抵抗力，显示出0.26%的减少，而WT巨噬细胞则显示出0.60%的减少。巨噬细胞中GsdmD的表达以IL-1β依赖性方式加剧泡沫细胞形成。GsdmD-/-小鼠对RCT中的Nlrp 3炎性体介导的缺陷具有抗性，其中血浆RCT减少了1032%，而WT小鼠中减少了1057%，肝脏RCT减少了1017%，而WT小鼠中减少了42%，粪便RCT减少了1037%，而WT小鼠中减少了1061%。用LDL r反义寡核苷酸（阿索）诱导的高脂血症小鼠模型显示GsdmD在促进动脉粥样硬化中的作用。与WT小鼠相比，GsdmD-/-小鼠在雌性中表现出动脉粥样硬化病变面积减少约42%，在雄性中表现出病变面积减少约33%。动脉粥样硬化斑块承载部分染色阳性裂解的N-末端片段的GsdmD，表明裂解的GsdmD在动脉粥样硬化斑块。我们的数据表明，GsdmD介导炎症诱导的RCT缺陷，并促进动脉粥样硬化。
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-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/AIM2 and IL-1β 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 ∼80% less IL-1β vs. Wild type (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 resistant 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 antisense oligonucleotides (ASO) induced hyperlipidemic mouse model showed the 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 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.
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影响因子：
32.4
作者：
Evavold CL;Ruan J;Tan Y;Xia S;Wu H;Kagan JC
通讯作者：
Kagan JC
影响因子：
37.8
作者：
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Komuro, Issei
影响因子：
21.3
作者：
Feng, B;Yao, PM;Tabas, I
通讯作者：
Tabas, I
DOI：
10.1056/nejmoa1701719
发表时间：
2017-07-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
Jaiswal S;Natarajan P;Silver AJ;Gibson CJ;Bick AG;Shvartz E;McConkey M;Gupta N;Gabriel S;Ardissino D;Baber U;Mehran R;Fuster V;Danesh J;Frossard P;Saleheen D;Melander O;Sukhova GK;Neuberg D;Libby P;Kathiresan S;Ebert BL
通讯作者：
Ebert BL
影响因子：
64.8
作者：
Ding, Jingjin;Wang, Kun;Shao, Feng
通讯作者：
Shao, Feng