Permanent neuroglial remodeling of the retina following infiltration of CSF1R inhibition-resistant peripheral monocytes

• Published in: Proceedings of the National Academy of Sciences - PNAS 2018-11, Vol.115 (48), p.E11359-E11368
• Main Authors: Paschalis, Eleftherios I., Lei, Fengyang, Zhou, Chengxin, Kapoulea, Vassiliki, Dana, Reza, Chodosh, James, Vavvas, Demetrios G., Βάββας, Δημήτριoς Γ., Dohlman, Claes H.
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Bone marrow; Cell Differentiation - drug effects; Central nervous system; Colony-stimulating factor; Degeneration; Depletion; Eye Injuries - genetics; Eye Injuries - immunology; Eye Injuries - physiopathology; Female; Glia; Humans; IL-1β; Immunology; Infiltration; Inflammation; Inhibition; Inhibitors; Injuries; Interleukin-1beta - genetics; Interleukin-1beta - immunology; Leukocytes; Macrophage colony-stimulating factor; Major histocompatibility complex; Male; Mice; Microglia; Monocytes; Monocytes - cytology; Monocytes - drug effects; Monocytes - immunology; Morphology; Nervous system; Neurodegeneration; Neuroglia; Neuroglia - cytology; Neuroglia - drug effects; Neuroglia - immunology; PNAS Plus; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - antagonists & inhibitors; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Retina; Retina - drug effects; Retina - immunology; Retinal degeneration; Small Molecule Libraries - pharmacology; Tumor necrosis factor-α
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1807123115

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.