Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signaling.
Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signaling.
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DOI：
10.1172/jci.insight.138539
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发表时间：
2022-11-22
期刊：
影响因子：
8
通讯作者：
Oishi, Yumiko
中科院分区：
文献类型：
--
作者：
Hayakawa, Sumio;Tamura, Atsushi;Nikiforov, Nikita;Koike, Hiroyuki;Kudo, Fujimi;Cheng, Yinglan;Miyazaki, Takuro;Kubekina, Marina;Kirichenko, Tatiana, V;Orekhov, Alexander N.;Yui, Nobuhiko;Manabe, Ichiro;Oishi, Yumiko
最近的研究表明，细胞代谢与免疫细胞的调节密切相关。在这里，我们发现胆固醇代谢的激活，包括胆固醇摄取、合成和自噬/脂噬，是巨噬细胞先天免疫反应的组成部分。特别是，内体和溶酶体内的胆固醇积累是toll样受体4激活引起的细胞胆固醇动力学的标志，也是髓系分化初级反应88 （Myd88）信号放大所必需的。从机制上讲，Myd88通过其CLR识别/相互作用氨基酸共识结构域与胆固醇结合，从而促进蛋白质的自寡聚化。此外，一种新的超分子化合物聚轮烷（PRX）通过促进胆固醇运输和外排来降低内溶酶体胆固醇，从而抑制Myd88依赖性炎症巨噬细胞的激活。PRX激活肝脏X受体，导致ATP结合盒转运蛋白A1上调，从而促进胆固醇外排。PRX还能抑制Ldlr - / -小鼠的动脉粥样硬化。在人类中，循环单核细胞中的胆固醇水平与动脉粥样硬化的严重程度呈正相关。这些发现表明，胆固醇代谢的动态变化与巨噬细胞中Myd88依赖性炎症程序的机制相关，并支持细胞胆固醇代谢是巨噬细胞先天激活不可或缺的概念，并且是炎症性疾病的潜在治疗和诊断靶点。
Recent studies have shown that cellular metabolism is tightly linked to the regulation of immune cells. Here, we show that activation of cholesterol metabolism, involving cholesterol uptake, synthesis, and autophagy/lipophagy, is integral to innate immune responses in macrophages. In particular, cholesterol accumulation within endosomes and lysosomes is a hallmark of the cellular cholesterol dynamics elicited by Toll-like receptor 4 activation and is required for amplification of myeloid differentiation primary response 88 (Myd88) signaling. Mechanistically, Myd88 binds cholesterol via its CLR recognition/interaction amino acid consensus domain, which promotes the protein’s self-oligomerization. Moreover, a novel supramolecular compound, polyrotaxane (PRX), inhibited Myd88‑dependent inflammatory macrophage activation by decreasing endolysosomal cholesterol via promotion of cholesterol trafficking and efflux. PRX activated liver X receptor, which led to upregulation of ATP binding cassette transporter A1, thereby promoting cholesterol efflux. PRX also inhibited atherogenesis in Ldlr–/– mice. In humans, cholesterol levels in circulating monocytes correlated positively with the severity of atherosclerosis. These findings demonstrate that dynamic changes in cholesterol metabolism are mechanistically linked to Myd88‑dependent inflammatory programs in macrophages and support the notion that cellular cholesterol metabolism is integral to innate activation of macrophages and is a potential therapeutic and diagnostic target for inflammatory diseases.
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影响因子：
3.4
作者：
Guo M;Härtlova A;Dill BD;Prescott AR;Gierliński M;Trost M
通讯作者：
Trost M
影响因子：
12.6
作者：
Hu YB;Dammer EB;Ren RJ;Wang G
通讯作者：
Wang G
动脉粥样硬化的炎症。
DOI：
10.1161/atvbaha.108.179705
发表时间：
2012-09
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Libby P
通讯作者：
Libby P
影响因子：
7.7
作者：
Ito A;Hong C;Rong X;Zhu X;Tarling EJ;Hedde PN;Gratton E;Parks J;Tontonoz P
通讯作者：
Tontonoz P
DOI：
10.1016/s0005-2760(98)00178-7
发表时间：
1999-01-29
影响因子：
4.8
作者：
Avdulov, NA;Chochina, SV;Wood, WG
通讯作者：
Wood, WG