Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114;
Boston Keratoprosthesis Laboratory, Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114.
Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):E11359-E11368. doi: 10.1073/pnas.1807123115. Epub 2018 Nov 15.
Previous studies have demonstrated that ocular injury can lead to prompt infiltration of bone-marrow-derived peripheral monocytes into the retina. However, the ability of these cells to integrate into the tissue and become microglia has not been investigated. Here we show that such peripheral monocytes that infiltrate into the retina after ocular injury engraft permanently, migrate to the three distinct microglia strata, and adopt a microglia-like morphology. In the absence of ocular injury, peripheral monocytes that repopulate the retina after depletion with colony-stimulating factor 1 receptor (CSF1R) inhibitor remain sensitive to CSF1R inhibition and can be redepleted. Strikingly, consequent to ocular injury, the engrafted peripheral monocytes are resistant to depletion by CSF1R inhibitor and likely express low CSF1R. Moreover, these engrafted monocytes remain proinflammatory, expressing high levels of MHC-II, IL-1β, and TNF-α over the long term. The observed permanent neuroglia remodeling after injury constitutes a major immunological change that may contribute to progressive retinal degeneration. These findings may also be relevant to other degenerative conditions of the retina and the central nervous system.
先前的研究表明，眼部损伤可导致骨髓来源的外周单核细胞迅速浸润到视网膜中。然而，这些细胞整合到组织中并成为小胶质细胞的能力尚未得到研究。在这里，我们发现，眼部损伤后浸润到视网膜中的这些外周单核细胞能够永久定植，迁移到三个不同的小胶质细胞层，并呈现小胶质细胞样形态。在没有眼部损伤的情况下，用集落刺激因子 1 受体 (CSF1R) 抑制剂耗竭后再由外周单核细胞填充的视网膜仍对 CSF1R 抑制剂敏感，并可再次耗竭。引人注目的是，继眼部损伤后，植入的外周单核细胞对 CSF1R 抑制剂的耗竭具有抗性，并且可能表达低水平的 CSF1R。此外，这些植入的单核细胞在长期内仍保持促炎状态，高水平表达 MHC-II、IL-1β 和 TNF-α。损伤后观察到的永久性神经胶质重塑构成了一个主要的免疫变化，可能导致进行性视网膜变性。这些发现可能与视网膜和中枢神经系统的其他退行性疾病也有关。
