microRNA-33 deficiency in macrophages enhances autophagy, improves mitochondrial homeostasis, and protects against lung fibrosis.
microRNA-33 deficiency in macrophages enhances autophagy, improves mitochondrial homeostasis, and protects against lung fibrosis.
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巨噬细胞中的microRNA-33缺陷增强自噬，改善线粒体稳态，并防止肺纤维化。
DOI：
10.1172/jci.insight.158100
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发表时间：
2023-02-22
期刊：
影响因子：
8
通讯作者：
Kaminski, Naftali
中科院分区：
文献类型：
--
作者：
Ahangari, Farida;Price, Nathan L.;Malik, Shipra;Chioccioli, Maurizio;Barnthaler, Thomas;Adams, Taylor S.;Kim, Jooyoung;Pradeep, Sai Pallavi;Ding, Shuizi;Cosmos Jr., Carlos;Rose, Kadi-Ann S.;McDonough, John E.;Aurelien, Nachelle R.;Ibarra, Gabriel;Omote, Norihito;Schupp, Jonas C.;DeIuliis, Giuseppe;Nunez, Julian A. Villalba;Sharma, Lokesh;Ryu, Changwan;Dela Cruz, Charles S.;Liu, Xinran;Prasse, Antje;Rosas, Ivan;Bahal, Raman;Fernandez-Hernando, Carlos;Kaminski, Naftali
特发性肺纤维化（IPF）是一种进行性的最终致死性疾病。最近的研究结果表明，肺纤维化过程中线粒体稳态和自噬的变化与显著的代谢重编程有关。在固醇调节元件结合蛋白（SREBP）基因的内含子内编码的microRNA-33（miR-33）家族的microRNA（miRNA）是固醇和脂肪酸（FA）代谢的主要调节因子。miR-33控制巨噬细胞免疫代谢反应，并增强线粒体生物合成、FA氧化和胆固醇流出。在这里，我们发现，与健康对照相比，从IPF患者中分离的支气管肺泡灌洗（BAL）细胞中的miR-33水平增加。我们证明了巨噬细胞中miR-33的特异性基因消融可以保护博来霉素诱导的肺纤维化。巨噬细胞中miR-33的缺乏改善了线粒体稳态并增加了自噬，同时降低了博来霉素损伤后的炎症反应。值得注意的是，通过施用抗miR-33肽核酸（PNA-33）对巨噬细胞中的miR-33的药理学抑制减弱了肺纤维化的不同体内和离体小鼠和人模型中的纤维化。这些研究阐明了巨噬细胞中miR-33在调节肺纤维化中的主要作用，并揭示了治疗这种疾病的潜在新治疗方法。
Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. Recent findings have shown a marked metabolic reprogramming associated with changes in mitochondrial homeostasis and autophagy during pulmonary fibrosis. The microRNA-33 (miR-33) family of microRNAs (miRNAs) encoded within the introns of sterol regulatory element binding protein (SREBP) genes are master regulators of sterol and fatty acid (FA) metabolism. miR-33 controls macrophage immunometabolic response and enhances mitochondrial biogenesis, FA oxidation, and cholesterol efflux. Here, we show that miR-33 levels are increased in bronchoalveolar lavage (BAL) cells isolated from patients with IPF compared with healthy controls. We demonstrate that specific genetic ablation of miR-33 in macrophages protects against bleomycin-induced pulmonary fibrosis. The absence of miR-33 in macrophages improves mitochondrial homeostasis and increases autophagy while decreasing inflammatory response after bleomycin injury. Notably, pharmacological inhibition of miR-33 in macrophages via administration of anti–miR-33 peptide nucleic acids (PNA-33) attenuates fibrosis in different in vivo and ex vivo mice and human models of pulmonary fibrosis. These studies elucidate a major role of miR-33 in macrophages in the regulation of pulmonary fibrosis and uncover a potentially novel therapeutic approach to treat this disease.
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巨噬细胞线粒体能量状态调节胆固醇外排，并在动脉粥样硬化中通过抗MIR33增强。
影响因子：
20.1
作者：
Karunakaran D;Thrush AB;Nguyen MA;Richards L;Geoffrion M;Singaravelu R;Ramphos E;Shangari P;Ouimet M;Pezacki JP;Moore KJ;Perisic L;Maegdefessel L;Hedin U;Harper ME;Rayner KJ
通讯作者：
Rayner KJ
影响因子：
5.8
作者：
Lehmann M;Buhl L;Alsafadi HN;Klee S;Hermann S;Mutze K;Ota C;Lindner M;Behr J;Hilgendorff A;Wagner DE;Königshoff M
通讯作者：
Königshoff M
影响因子：
20.1
作者：
Afonso MS;Sharma M;Schlegel M;van Solingen C;Koelwyn GJ;Shanley LC;Beckett L;Peled D;Rahman K;Giannarelli C;Li H;Brown EJ;Khodadadi-Jamayran A;Fisher EA;Moore KJ
通讯作者：
Moore KJ
DOI：
10.1161/atvbaha.115.306404
发表时间：
2015-12
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Karunakaran D;Richards L;Geoffrion M;Barrette D;Gotfrit RJ;Harper ME;Rayner KJ
通讯作者：
Rayner KJ
影响因子：
4.4
作者：
Kobayashi, Kenji;Araya, Jun;Kuwano, Kazuyoshi
通讯作者：
Kuwano, Kazuyoshi