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Fengyang Lei, Chengxin Zhou, Claes H Dohlman, Reza Dana, James Chodosh, Demetrios Vavvas, Eleftherios I Paschalis; Permanent neuroglial remodeling after acute ocular injury. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3992.
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Acute eye injury may lead to inflammation, retinal damage, and glaucoma. However, the role of peripheral monocytes and retinal microglia in this process remains largely unknown. The purpose of this study is to investigate the involvement of peripheral monocytes and resident microglia in the ensued retinal neurodegeneration following acute eye injury.
Three different ocular injury models were employed: a) ocular surface alkali burn using 2N NaOH on a filter paper delivered to the cornea for 20 sec, b) ocular hypertension using 33G needle for cannulation at 80mmHg for 50 min, and c) penetrating corneal injury using a 11-0 corneal suture. To distinguish peripheral macrophages from resident microglia, we used CCR2RFP/+::CX3CR1GFP/+ double reporter chimera mouse. To dissect the function of retinal microglia, a small molecule CSF1R inhibitor (PLX5622) was employed for their depletion.
All three ocular injuries caused infiltration of peripheral CCR2+ CX3CR1+ monocytes into the retina and permanent engraftment. Infiltrated monocytes gradually migrated into all three distinct microglia strata and differentiated from CCR2+::CX3CR1+ to CCR2-negative::CX3CR1+ cells. Peripheral monocytes adopted a quiescent ‘microglia-like’ morphology but remained pro-inflammatory expressing high levels of MHC-II, TNF-α, and IL-1β, and phagocytosed neuronal tissue even months after the injury. Microglia depletion prior to the injury led to abnormal repopulation by peripheral monocytes, exacerbating neuroretinal damage. Furthermore, after ocular injury, peripherally engrafted monocytes were transcriptionally distinct from resident microglia, expressing low CSF1R surface marker, and did not respond to recombinant CSF1R and IL-4 stimulation.
Acute ocular injury leads to a significant alteration in retinal microglia homeostasis, with an influx of peripherally-derived monocytes that engraft permanently and acquire ‘microglia-like’ morphology. These cells, despite their morphometric quiescence, remain pro-inflammatory and contribute to chronic progressive retina degeneration long after the injury has occurred. Resident microglia are key regulators of this process, suppressing inflammation and neurodegeneration. Future therapeutic strategies should focus on “retraining” of peripheral monocytes to acquire neuroprotective functions.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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