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Eleftherios I Paschalis, Fengyang Lei, Chengxin Zhou, Claes H Dohlman, Reza Dana, James Chodosh, Demetrios Vavvas; Peripheral monocyte are involved in permanent retinal neuroglia remodeling after injury.. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2799.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the cellular and molecular mechanisms involved in neuroglia remodeling after ocular injury.
Double reporter CX3CR1+/EGF::CCR2+/RFP, CX3CR1+/EGF::Thy1.1+/YFP, and CCR2+/RFP::Thy1.1+/YFPchimeras were generated for fate mapping. Colony stimulating factor 1 receptor inhibitor (PLX5622) was used to deplete the microglia. Four different ocular injury models were employed to initiate an inflammatory response a) ocular hypertension, b) penetrating surgical injury, c) penetrating keratoplasty, and d) optic nerve crush (ONC). Molecular and cellular analysese were performed with flow cytometry, qPCR, RNAseq, and microscopy.
All ocular injuries, except ONC, caused permeant engraftment of peripheral CCR2+CX3CR1+monocytes into the retina, which differentiated into CCR2-CX3CR1+microglia-like cells and migrated into the three distinct microglia strata. Patrolling CCR2+CX2CR1-peripheral monocytes were identified as an alternative pool of resident monocytes that gave rise to resident macrophages after injury. Although engrafted monocytes adopted a microglia-like morphology they remained transcriptionally distinct, expressing high levels of MHC-II, Tnf-α and Il-1β, and were not responsive to stimulation with Csf1 and Il-4. Resident retina microglia were shown to regulate monocyte engraftment and their depletion caused retinal inflammation, abnormal repopulation by peripheral monocytes, increased loss of Thy1+ neurons and increased retinal pigmentation. Strikingly and in contrast to all other injuries that led to RGC loss, ONC injury–mediated retinal ganglion cell loss did not evoke neither peripheral monocyte infiltration nor retinal pigmentation, although peripheral CX3CR1+ and CCR2+monocytes infiltrated the optic nerve injury site and remained present for months.
In contrast to previously held belief, peripheral monocytes are involved in permanent neuroglia remodeling after injury, and damage to the neuroretina. The lack of such response after ONC points to the existence of distinct regulatory microglia/monocyte mechanism. Interestingly, microglia depletion promotes retinal inflammation and neuronal damage post trauma. The retention of distinct proinflammatory signature of the peripherally engrafted monocytes constitutes a major immunological shift that may contribute to progressive neurodegeneration and glaucoma.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
Engrafted peripheral CX3CR1+monocytes 16 months after injury.
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