LAUSR

Significance 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.