M2 Macrophages Enhance Pathological Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy
M2 Macrophages Enhance Pathological Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy
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DOI：
10.1167/iovs.14-16012
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发表时间：
2015-07-01
影响因子：
4.4
通讯作者：
Ishibashi, Tatsuro
中科院分区：
文献类型：
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作者：
Zhou, Yedi;Yoshida, Shigeo;Ishibashi, Tatsuro
目的.探讨M2巨噬细胞在小鼠氧诱导视网膜病变（OIR）模型中的作用。通过将出生后第7天（P7）的幼仔暴露于75%的氧气，然后在P12时将其返回到室内空气中，在C57 BL/6 J小鼠中诱导氧诱导的视网膜病变。实时荧光定量PCR和免疫荧光染色用于评估不同巨噬细胞标志物的水平和分布。在P12时将骨髓源性M1和M2巨噬细胞和甘露糖基化氯膦酸盐脂质体（MCL）注射到玻璃体中，以检查P17时的作用。将M2巨噬细胞与人视网膜内皮细胞（HREC）共培养，以检查其对增殖和管形成的影响。结果表明，M2巨噬细胞，而不是M1表型，在OIR小鼠中高表达。M2巨噬细胞的数量在P17时显著增加，并且该增加与OIR视网膜中新生血管簇的存在密切相关。选择性去除M2巨噬细胞可抑制病理性新生血管形成，促进生理性血管重建。相反，玻璃体内注射骨髓源性M2巨噬细胞或培养上清液促进病理性新生血管形成并抑制生理性血管再生。在体外共培养体系中，M2极化的巨噬细胞可显著促进HREC增殖和管腔形成。这些结果表明，M2巨噬细胞，而不是M1，可能通过产生分泌因子在促进视网膜病理性新生血管形成中起重要作用。因此，靶向M2巨噬细胞可能是抑制视网膜病理性新生血管形成的潜在治疗选择。
PURPOSE. To investigate the roles played by M2 macrophages in a mouse model of oxygen-induced retinopathy (OIR).METHODS. Oxygen-induced retinopathy was induced in C57BL/6J mice by exposing postnatal day seven (P7) pups to 75% oxygen and then returning them to room air at P12. Real-time RTPCR and immunofluorescence staining were used to assess the levels and distributions of different macrophage markers. Bone marrow-derived M1 and M2 macrophages and mannosylated clodronate liposomes (MCLs) were injected into the vitreous on P12 to examine the effects at P17. M2 macrophages were cocultured with human retinal endothelial cells (HRECs) to examine their effects on proliferation and tube formation.RESULTS. The results showed that the M2 macrophages, rather than M1 phenotype, were highly expressed in OIR mice. The number of M2 macrophages had increased significantly at P17, and the increase was closely associated with the presence of neovascular tufts in the OIR retinas. Selective depletion of M2 macrophages suppressed the pathological neovascularization and promoted physiological revascularization. In contrast, intravitreal injection of bone marrow-derived M2 macrophages or the culture supernatants promoted pathological neovascularization and inhibited physiological revascularization. In an in vitro coculture system, M2-polarized macrophages significantly promoted proliferation and tube formation of HRECs.CONCLUSIONS. These results indicated that M2 macrophages, rather than M1, play an important role in promoting retinal pathological neovascularization probably by producing secreted factors. Thus, targeting M2 macrophages could be a potential therapeutic option for inhibiting retinal pathological neovascularization.