Up-Regulation of Matrix Metalloproteinase-2 by Scleral Monocyte-Derived Macrophages Contributes to Myopia Development
Up-Regulation of Matrix Metalloproteinase-2 by Scleral Monocyte-Derived Macrophages Contributes to Myopia Development
复制标题
巩膜单核细胞衍生的巨噬细胞上调基质金属蛋白酶-2 有助于近视发展
DOI：
10.1016/j.ajpath.2020.06.002
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发表时间：
2020-09-01
影响因子：
6
通讯作者：
Zhou, Xiangtian
中科院分区：
文献类型：
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作者：
Zhao, Fei;Wu, Hao;Zhou, Xiangtian
近视是世界范围内视力损害的主要原因。这种损害视力的情况与巩膜变薄、细胞外基质重塑和不适当的眼轴延长有关。虽然巩膜中存在巨噬细胞，但它们在这种情况下的参与尚不清楚。通过形觉剥夺性近视小鼠模型，我们发现近视眼的巩膜巨噬细胞密度及其基质金属蛋白酶-2的表达水平均升高。与注射赋形剂的对照组小鼠相比，部分去除巩膜巨噬细胞使形觉剥夺组和未治疗组小鼠的屈光转向远视。然而，这一过程并没有改变对fdm的易感性。巨噬细胞特异性MMP2缺失(LysM(Cre)MMP2(f1/f1))小鼠比其Cre阴性小鼠(MMP2(f1/f1)小鼠)少发生59%的fdm。此外，巩膜C-C基序趋化因子配体-2(CCL2)的表达在近视进展过程中增加，CCL2是一种强大的单核细胞趋化因子，将单核细胞招募到组织部位。然而，在成纤维细胞特异性CCL2缺失的小鼠中，巩膜巨噬细胞密度的增加和近视的发展受到抑制。这些下降表明近视眼巩膜巨噬细胞密度的增加源于成纤维细胞中巩膜CCL2表达的上调，这反过来又促进了单核细胞的募集。综上所述，巩膜单核细胞来源的巨噬细胞通过促进基质金属蛋白酶-2的表达促进近视的发展。
Myopia is a leading cause of visualimpairment worldwide. This sight-compromising condition is associated with scleral thinning, extracellular matrix remodeling, and inappropriate optical axial length elongation. Although macrophages are present in the sclera, their involvement in this condition is unknown. By using a form-deprivation myopia (FDM) mouse model, we found that both the scleral macro-phage density and their matrix metalloproteinase-2 (MMP-2) expression levels increased in myopic eyes. Partial scleral macrophage depletion by clodronate shifted the refraction toward hyperopia in both the form-deprived and the untreated fellow eyes compared with their respective counterparts in the vehicle-injected control mice. However, this procedure did not alter susceptibility to FDM. FDM development was 59% less in the macrophage-specific Mmp2 deletion (LysM(Cre)Mmp-2(fl/fl)) mice than in their Cre-negative littermates (Mmp2(fl/fl) mice). Moreover, the expression of scleral C-C motif chemokine ligand-2 (CCL2), which is a potent monocyte chemoattractant recruiting monocytes to tissue sites, was increased during myopia progression. However, the increase in the density of scleral macrophages and myopia development were suppressed in fibroblast-specific Ccl2 deletion mice. These declines suggested that the increase in scleral macrophage density in myopic eyes stems from the up-regulation of scleral Ccl2 expression in fibroblasts, which, in turn, promotes monocytes recruitment. In summary, scleral monocyte-derived macrophages contribute to myopia development through enhancing MMP-2 expression in mice.