Fibroblast transdifferentiation promotes conversion of M1 macrophages and replenishment of cardiac resident macrophages following cardiac injury in mice
Fibroblast transdifferentiation promotes conversion of M1 macrophages and replenishment of cardiac resident macrophages following cardiac injury in mice
复制标题
成纤维细胞转分化促进小鼠心脏损伤后 M1 巨噬细胞的转化和心脏常驻巨噬细胞的补充
DOI：
10.1002/eji.201948414
复制
发表时间：
2020
影响因子：
5.4
通讯作者：
Zhaoliang Su
中科院分区：
文献类型：
--
作者：
Hongxiang Lu;Rong Chen;Prince Amoah Barnie;Yu Tian;Shiqing Zhang;Huaxi Xu;Subrata Chakrabarti;Zhaoliang Su
驻留心脏巨噬细胞在体内平衡、维持心脏功能和组织修复中起重要作用。心脏损伤后，单核细胞浸润组织，经历表型和功能变化，并参与炎性损伤和功能重塑。然而，心脏浸润/极化巨噬细胞的命运以及这些细胞与损伤后常驻心脏巨噬细胞补充之间的关系仍不清楚。我们的研究结果表明，血管紧张素II诱导心肌成纤维细胞转分化为心肌成纤维细胞（MFB）。在与MFB和小鼠巨噬细胞的共培养中，MFB促进巨噬细胞极化为M1表型，随后选择性凋亡，这与TNF/TNFR 1轴相关，而不依赖于NO的产生。令人惊讶的是，在共培养36小时后，存活的巨噬细胞转化为M2表型并定居在心脏中，这依赖于由MFB或极化的巨噬细胞通过PI 3 K或Akt途径产生的瘦素。CCR 2 +CD45.2+细胞过继转移到患有病毒性心肌炎的CD45.1+小鼠中，在炎症消退期间分化为CD45.2+ CCR 2 + CX 3CR 1 + M2细胞并在心脏内定居。我们的数据强调了一种新的机制，与心脏损伤后心脏驻留巨噬细胞的更新或补充有关;并表明心脏成纤维细胞的转分化可能促进炎症的消退。
Resident cardiac macrophages play important roles in homeostasis, maintenance of cardiac function, and tissue repair. After cardiac injury, monocytes infiltrate the tissue, undergo phenotypic and functional changes, and are involved in inflammatory injury and functional remodelling. However, the fate of cardiac infiltrating/polarized macrophages and the relationship between these cells and resident cardiac macrophage replenishment following injury remain unclear. Our results showed that angiotensin II induces cardiac fibroblast transdifferentiation into cardiac myofibroblasts (MFBs). In cocultures with MFBs and murine macrophages, the MFBs promoted macrophage polarization to M1 phenotype, followed by selective apoptosis, which was associated with TNF/TNFR1 axis and independent of NO production. Surprisingly, after 36 h of coculture, the surviving macrophages were converted to M2 phenotype and settled in heart, which was dependent on leptin produced by MFBs or polarized macrophages via the PI3K or Akt pathway. CCR2+CD45.2+ cells adoptively transferred into CD45.1+ mice with viral myocarditis, differentiated into CD45.2+CCR2+CX3CR1+ M2 cells during the resolution of inflammation and settled within the heart. Our data highlight a novel mechanism related to the renewal or replenishment of cardiac resident macrophages following cardiac injury; and suggest that transdifferentiation of cardiac fibroblasts may promote the resolution of inflammation.