Antiinflammatory activity of ANGPTL4 facilitates macrophage polarization to induce cardiac repair
Antiinflammatory activity of ANGPTL4 facilitates macrophage polarization to induce cardiac repair
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DOI：
10.1172/jci.insight.125437
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发表时间：
2019-08-22
期刊：
影响因子：
8
通讯作者：
Ahn, Youngkeun
中科院分区：
文献类型：
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作者：
Cho, Dong Im;Kong, Hye-jin;Ahn, Youngkeun
间充质干细胞(MSCs)可以抑制病理性炎症。然而，MSCs与炎症之间的联系的潜在机制仍不清楚。在与巨噬细胞共培养的条件下，MSCs高表达血管生成素样4(ANGPTL4)，以钝化巨噬细胞向促炎表型的极化。ANGPTL4基因缺陷的MSCs不能抑制炎性巨噬细胞表型。在炎症相关的动物模型中。注射共培养基或ANGPTL4蛋白可增加腹膜炎和心肌梗死大鼠的抗炎巨噬细胞数量。尤其是ANGPTL4治疗后心功能和病理均有明显改善。我们发现维甲酸相关的孤儿受体α(RORα)在炎症介质如IL-1β的作用下增加，并与MSCs中的ANGPTL4启动子结合。总之，在病理条件下，RORα介导的ANGPTL4诱导被证明有助于MSCs对巨噬细胞的抗炎活性。这项研究表明，从翻译的角度来看，ANGPTL4诱导组织修复的能力是安全的无干细胞再生治疗的一个有希望的机会。
Mesenchymal stem cells (MSCs) can suppress pathological inflammation. However, the mechanisms underlying the association between MSCs and inflammation remain unclear. Under coculture conditions with macrophages, MSCs highly expressed angiopoietin- like 4 (ANGPTL4) to blunt the polarization of macrophages toward the proinflammatory phenotype. ANGPTL4-deficient MSCs failed to inhibit the inflammatory macrophage phenotype. In inflammation-related animal models. the injection of coculture medium or ANGPTL4 protein increased the antiinflammatory macrophages in both peritonitis and myocardial infarction. In particular, cardiac function and pathology were markedly improved by ANGPTL4 treatment. We found that retinoic acid-related orphan receptor alpha (ROR alpha) was increased by inflammatory mediators, such as IL-1 beta, and bound to ANGPTL4 promoter in MSCs. Collectively, ROR alpha -mediated ANGPTL4 induction was shown to contribute to the antiinflammatory activity of MSCs against macrophages under pathological conditions. This study suggests that the capability of ANGPTL4 to induce tissue repair is a promising opportunity for safe stem cell-free regeneration therapy from a translational perspective.