Targeting macrophage TFEB-14-3-3 epsilon Interface by naringenin inhibits abdominal aortic aneurysm.
Targeting macrophage TFEB-14-3-3 epsilon Interface by naringenin inhibits abdominal aortic aneurysm.
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柚皮素靶向巨噬细胞 TFEB-14-3-3 epsilon 界面抑制腹主动脉瘤
DOI：
10.1038/s41421-021-00363-1
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发表时间：
2022-03-01
期刊：
影响因子：
33.5
通讯作者：
Kong W
中科院分区：
文献类型：
--
作者：
Jia Y;Zhang L;Liu Z;Mao C;Ma Z;Li W;Yu F;Wang Y;Huang Y;Zhang W;Zheng J;Wang X;Xu Q;Zhang J;Feng W;Yun C;Liu C;Sun J;Fu Y;Cui Q;Kong W
腹主动脉瘤（AAA）是一种致命的心血管疾病，目前尚无有效的药物治疗方法。在这项研究中，通过使用连接图（CMap）的方法，我们探讨了柚皮素，一种天然存在的柑橘类黄酮，作为抑制AAA的推定代理。然后，我们用两个独立的AAA小鼠模型，磷酸钙（CaPO4）诱导的C57 BL/6J小鼠和血管紧张素II输注的ApoE −/−小鼠验证了预测。柚皮素有效地阻断了AAAs的形成和已建立的AAAs的进展。转录因子EB（TFEB）是溶酶体生物合成的主要调节因子。有趣的是，在小鼠中，通过巨噬细胞特异性TFEB消耗，柚皮素对AAA的保护作用被消除。结合等温滴定量热法（ITC）和细胞热位移测定（CETSAs）的无偏相互作用组学进一步揭示，柚皮素直接结合至14 - 3 - 3 β阻断TFEB-14 - 3 - 3 β相互作用，并因此促进TFEB核转位和活化。一方面，柚皮素激活了NLRP 3炎性小体的溶酶体依赖性抑制，并抑制了囊性炎症。另一方面，柚皮素诱导GATA 3、IRF 4和STAT 6的TFEB依赖性转录激活，因此促进修复性M2巨噬细胞极化。总之，天然衍生的柚皮素或巨噬细胞TFEB活化显示出治疗AAA的有希望的功效。
Abdominal aortic aneurysm (AAA) is a lethal cardiovascular disease, and there is no proven drug treatment for this condition. In this study, by using the Connectivity Map (CMap) approach, we explored naringenin, a naturally occurring citrus flavonoid, as a putative agent for inhibiting AAA. We then validated the prediction with two independent mouse models of AAA, calcium phosphate (CaPO4)-induced C57BL/6J mice and angiotensin II-infused ApoE−/− mice. Naringenin effectively blocked the formation of AAAs and the progression of established AAAs. Transcription factor EB (TFEB) is the master regulator of lysosome biogenesis. Intriguingly, the protective role of naringenin on AAA was abolished by macrophage-specific TFEB depletion in mice. Unbiased interactomics, combined with isothermal titration calorimetry (ITC) and cellular thermal shift assays (CETSAs), further revealed that naringenin is directly bound to 14-3-3 epsilon blocked the TFEB-14-3-3 epsilon interaction, and therefore promoted TFEB nuclear translocation and activation. On one hand, naringenin activated lysosome-dependent inhibition of the NLRP3 inflammasome and repressed aneurysmal inflammation. On the other hand, naringenin induced TFEB-dependent transcriptional activation of GATA3, IRF4, and STAT6 and therefore promoted reparative M2 macrophage polarization. In summary, naturally derived naringenin or macrophage TFEB activation shows promising efficacy for the treatment of AAA.
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影响因子：
10.8
作者：
Fornasa, Giulia;Clement, Marc;Caligiuri, Giuseppina
通讯作者：
Caligiuri, Giuseppina
影响因子：
2.2
作者：
Baxter BT;Matsumura J;Curci J;McBride R;Blackwelder WC;Liu X;Larson L;Terrin ML;N-TA(3)CT Investigators
通讯作者：
N-TA(3)CT Investigators
影响因子：
3.3
作者：
Annadurai, T.;Thomas, P. A.;Geraldine, P.
通讯作者：
Geraldine, P.
影响因子：
2.7
作者：
ABE, A;INOKUCHI, J;RADIN, NS
通讯作者：
RADIN, NS
影响因子：
2.3
作者：
Davis FM;Rateri DL;Daugherty A
通讯作者：
Daugherty A