Cholesterol Efflux Pathways Suppress Inflammasome Activation, NETosis, and Atherogenesis.
Cholesterol Efflux Pathways Suppress Inflammasome Activation, NETosis, and Atherogenesis.
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DOI：
10.1161/circulationaha.117.032636
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发表时间：
2018-08-28
期刊：
影响因子：
37.8
通讯作者：
Tall AR
中科院分区：
文献类型：
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作者：
Westerterp M;Fotakis P;Ouimet M;Bochem AE;Zhang H;Molusky MM;Wang W;Abramowicz S;la Bastide-van Gemert S;Wang N;Welch CL;Reilly MP;Stroes ES;Moore KJ;Tall AR
CANTOS试验显示，白细胞介素-1 β（IL-1β）拮抗剂可降低既往有心肌梗死和全身炎症证据的患者的冠心病，表明IL-1β分泌所需的途径增加心血管风险。IL-1β和IL-18通过髓样细胞中的NLRP 3炎性小体响应于胆固醇积累而产生，但将NLRP 3炎性小体活化与动脉粥样硬化形成联系起来的机制尚不清楚。胆固醇转运蛋白ATP结合盒A1和G1（ABCA 1/G1）介导胆固醇流出到高密度脂蛋白（HDL），并且骨髓细胞中的Abca 1/g1缺乏导致胆固醇蓄积。为了探究炎性体激活与动脉粥样硬化形成的机制，我们使用了骨髓Abca 1/g1缺陷和炎性体组分Nlrp 3或Caspase-1/11伴随缺陷的小鼠。这些小鼠的骨髓（BM）被移植到Ldlr−/−受体中，这些受体被喂食西式饮食（WTD）。髓样Abca 1/g1缺陷增加了Ldlr−/−小鼠的血浆IL-18水平，并诱导脾细胞分泌IL-1β和IL-18，这被Nlrp 3或Caspase-1/11缺陷逆转，表明NLRP 3炎性体活化。Nlrp 3或Caspase-1/11缺陷减少髓系Abca 1/g1缺陷Ldlr−/−小鼠动脉粥样硬化病变大小。髓样Abca 1/g1缺陷不仅在脾单核细胞和巨噬细胞中增强Caspase-1裂解，而且在中性粒细胞中增强Caspase-1裂解，并且显著增强动脉粥样硬化斑块中的中性粒细胞积聚和中性粒细胞胞外陷阱（NET）形成，Nlrp 3或Caspase-1/11缺陷逆转，表明炎性小体激活促进动脉粥样硬化斑块中的中性粒细胞募集和NETosis。这些作用似乎是由全身性炎症间接介导的，导致斑块中中性粒细胞的活化和蓄积。髓系Abca 1/g1缺陷也激活了非典型炎性小体，导致对LPS诱导的死亡率的易感性增加。携带ABCA 1功能缺失突变且髓样胆固醇含量增加的Tangier病患者显示血浆IL-1β和IL-18水平显著升高。骨髓细胞中胆固醇的积累激活NLRP 3炎性小体，这增强了动脉粥样硬化斑块中的中性粒细胞积累和NETosis。骨髓胆固醇含量增加的丹吉尔病患者显示炎性小体激活的标志物，表明与人类相关。
The CANTOS trial showed that antagonism of interleukin-1β (IL-1β) reduces coronary heart disease in patients with a previous myocardial infarction and evidence of systemic inflammation, indicating that pathways required for IL-1β secretion increase cardiovascular risk. IL-1β and IL-18 are produced via the NLRP3 inflammasome in myeloid cells in response to cholesterol accumulation, but mechanisms linking NLRP3 inflammasome activation to atherogenesis are unclear. The cholesterol transporters ATP Binding Cassette A1 and G1 (ABCA1/G1) mediate cholesterol efflux to high-density-lipoprotein (HDL) and Abca1/g1 deficiency in myeloid cells leads to cholesterol accumulation. To interrogate mechanisms connecting inflammasome activation with atherogenesis, we used mice with myeloid Abca1/g1 deficiency and concomitant deficiency of the inflammasome components Nlrp3 or Caspase-1/11. Bone marrow (BM) from these mice was transplanted into Ldlr−/− recipients, which were fed a Western-type diet (WTD). Myeloid Abca1/g1 deficiency increased plasma IL-18 levels in Ldlr−/− mice and induced IL-1β and IL-18 secretion in splenocytes, which was reversed by Nlrp3 or Caspase-1/11 deficiency, indicating activation of the NLRP3 inflammasome. Nlrp3 or Caspase-1/11 deficiency decreased atherosclerotic lesion size in myeloid Abca1/g1 deficient Ldlr−/− mice. Myeloid Abca1/g1 deficiency enhanced Caspase-1 cleavage not only in splenic monocytes and macrophages, but also in neutrophils, and dramatically enhanced neutrophil accumulation and neutrophil extracellular trap (NET) formation in atherosclerotic plaques, with reversal by Nlrp3 or Caspase-1/11 deficiency, suggesting that inflammasome activation promotes neutrophil recruitment and NETosis in atherosclerotic plaques. These effects appeared to be indirectly mediated by systemic inflammation leading to activation and accumulation of neutrophils in plaques. Myeloid Abca1/g1 deficiency also activated the non-canonical inflammasome causing increased susceptibility to LPS-induced mortality. Tangier Disease patients, who carry loss-of-function mutations in ABCA1 and have increased myeloid cholesterol content, showed a marked increase in plasma IL-1β and IL-18 levels. Cholesterol accumulation in myeloid cells activates the NLRP3 inflammasome, which enhances neutrophil accumulation and NETosis in atherosclerotic plaques. Tangier Disease patients, who have increased myeloid cholesterol content, showed markers of inflammasome activation, suggesting human relevance.