M2b Macrophages Regulate Cardiac Fibroblast Activation and Alleviate Cardiac Fibrosis After Reperfusion Injury
M2b Macrophages Regulate Cardiac Fibroblast Activation and Alleviate Cardiac Fibrosis After Reperfusion Injury
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M2b巨噬细胞调节心脏成纤维细胞活化并减轻再灌注损伤后的心脏纤维化
DOI：
10.1253/circj.cj-19-0959
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发表时间：
2020-04-01
影响因子：
3.3
通讯作者：
Wu, Zhongkai
中科院分区：
文献类型：
--
作者：
Yue, Yuan;Huang, Suiqing;Wu, Zhongkai
背景：巨噬细胞在心肌纤维化的发生发展中起重要作用。然而，不同的巨噬细胞亚型在心脏成纤维细胞(CF)激活和心肌纤维化中的作用尚不清楚。方法和结果：骨髓来源的巨噬细胞(BMDM)用不同的刺激诱导分化为M1、M2a、M2b和M2c巨噬细胞亚型。将CFs与不同亚型的巨噬细胞共同培养，或与巨噬细胞上清液共同培养。结果显示，M2B巨噬细胞显著抑制CFs的增殖和迁移，抑制纤维化相关蛋白(I型胶原[Col-1]和α-SMA)的表达，并抑制其向心肌成纤维细胞(MFS)的分化。而对M2a巨噬细胞的作用则相反。采用大鼠心肌缺血再灌注(I/R)损伤模型，观察M2B巨噬细胞移植的影响。心脏I/R损伤后，移植M2B巨噬细胞可改善心功能，减少心肌纤维化。免疫印迹法检测巨噬细胞亚型对p-ERK、ERK、p-p38和p38磷酸化的影响。结果表明，M2B巨噬细胞对丝裂原活化蛋白激酶(MAPK)信号通路有明显的抑制作用。结论：本研究首次证实了不同亚型巨噬细胞在调节CF活化中的不同作用。M2B巨噬细胞抑制CF的激活，因此可以被认为是抗纤维化的巨噬细胞。M2a巨噬细胞促进CF活化，因此是促纤维化的巨噬细胞。
Background: Macrophages play an important role in the development of cardiac fibrosis. However, the roles of different macrophage subtypes in cardiac fibroblast (CF) activation and cardiac fibrosis are unknown.Methods and Results: Bone marrow-derived macrophages (BMDMs) were treated with different stimuli to induce differentiation into M1, M2a, M2b, and M2c macrophage subtypes. CFs were co-cultured with different subtypes of macrophages or cultured with macrophage supernatants. Results revealed that M2b macrophages significantly suppressed the proliferation and migration of CFs, the expression of fibrosis-related proteins (collagen I [COL-1] and alpha-smooth muscle actin [alpha-SMA]), and differentiation into cardiac myofibroblasts (MFs). The opposite effects were observed with M2a macrophages. A rat model of cardiac ischemia/reperfusion (I/R) injury was used to determine the effect of M2b macrophages transplantation. After cardiac I/R injury, transplantation of M2b macrophages improved cardiac function and reduced cardiac fibrosis. The effect of macrophage subtypes on p-ERK, ERK, p-p38, and p38 phosphorylation was examined by Western blotting. The results showed that M2b macrophages significantly inhibited the mitogen-activated protein kinase (MAPK) signaling pathway.Conclusions: These study results demonstrate for the first time that different subtypes of macrophages have different roles in regulating CF activation. M2b macrophages inhibit CF activation, and thus can be considered anti-fibrotic macrophages. M2a macrophages promote CF activation, and thus are pro-fibrotic macrophages.