Permanent neuroglial remodeling of the retina following infiltration of CSF1R inhibition-resistant peripheral monocytes.
Permanent neuroglial remodeling of the retina following infiltration of CSF1R inhibition-resistant peripheral monocytes.
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DOI：
10.1073/pnas.1807123115
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发表时间：
2018-11-27
影响因子：
11.1
通讯作者：
Dohlman CH
中科院分区：
文献类型：
--
作者：
Paschalis EI;Lei F;Zhou C;Kapoulea V;Dana R;Chodosh J;Vavvas DG;Dohlman CH
这项工作有助于理解急性眼表损伤后神秘的进行性视网膜损伤。患者的临床结果表明，这种损伤会对视网膜产生不利影响。本研究表明，角膜损伤导致血源性单核细胞快速浸润到视网膜，随后神经胶质系统重塑。与先前的观点相反，这项研究表明，血液来源的单核细胞永久性地植入视网膜并分化成小胶质样细胞。尽管这些细胞在形态上与天然小胶质细胞难以区分，但它们保留了独特的特征，对CSF1R抑制不敏感，并表现出反应性表型，这种表型在有害刺激去除后很长时间内持续存在，最终导致进行性神经视网膜变性。先前的研究表明，眼损伤可导致骨髓来源的外周单核细胞迅速浸润到视网膜。然而，这些细胞融入组织并成为小胶质细胞的能力尚未被研究。本研究表明，眼损伤后浸润到视网膜的外周单核细胞永久性移植，迁移到三种不同的小胶质细胞层，并呈现小胶质样形态。在没有眼部损伤的情况下，用集落刺激因子1受体（CSF1R）抑制剂去除后重新填充视网膜的外周单核细胞对CSF1R抑制仍然敏感，并且可以重新耗尽。引人注目的是，由于眼部损伤，移植的外周单核细胞对CSF1R抑制剂的消耗具有抗性，并且可能表达低CSF1R。此外，这些植入的单核细胞仍然具有促炎作用，长期表达高水平的MHC-II、IL-1β和TNF-α。损伤后观察到的永久性神经胶质细胞重塑构成了可能导致进行性视网膜变性的主要免疫改变。这些发现也可能与视网膜和中枢神经系统的其他退行性疾病有关。
This work contributes to the understanding of the enigmatic progressive retinal damage following acute ocular surface injury. Clinical findings in patients suggest that such injuries can adversely affect the retina. This study demonstrates that corneal injury leads to rapid infiltration of blood-derived monocytes into the retina and to subsequent remodeling of the neuroglial system. In contrast to previously held belief, this study shows that the blood-derived monocytes engraft permanently into the retina and differentiate into microglia-like cells. Although these cells are morphologically indistinguishable from native microglia, they retain a distinct signature and insensitivity to CSF1R inhibition and exhibit a reactive phenotype which persists long after the noxious stimuli is removed, ultimately contributing to progressive neuroretinal degeneration. 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.
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