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

Abstract

SignificanceThis 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.

Reply to Green and Hume: Nonmicroglia peripheral immune effects of short-term CSF1R inhibition with PLX5622

“…We reject the comment by Green and Hume ( 4 ) that PLX5622 dose and duration was not provided or that it was selected arbitrarily. A careful reading of our paper ( 1 ) and the literature reveals this information, which is in concordance with at least 14 papers using exactly the same dose (PLX5622 chow, 1,200 ppm) and duration (3 wk) ( 1 – 3 , 5 ), some of which have been cited by Green et al ( 6 ) in a prior review. † For the benefit of the community, we provide additional data in this Reply showing that even short-term (7 d or 10 d) treatment with PLX5622 results in similar nonmicroglia changes ( Figs.…”

“…Many microglia papers have assumed or claimed that CSFR1 inhibition has no to minimal effects on peripheral immune cells. * The nonmicroglia effects of CSFR1 inhibition have direct ramifications for the interpretation of relevant experimental data; peripheral monocytes/macrophages engraft permanently into the retina after PLX5622 treatment ( 2 , 3 ), causing remodeling and functional changes that affect studied outcome.…”

When Is a Control Not a Control? Reactive Microglia Occur Throughout the Control Contralateral Pathway of Retinal Ganglion Cell Projections in Experimental Glaucoma

“…Extravasation and increased monocyte infiltration have been demonstrated as an early and persistent feature of glaucoma in animal models 33 and in post mortem human tissue, 2 and CD45 hi monocytes are present in the retina in low numbers under normal physiologic conditions. 34 , 35 We observed IsoB4+ fully amoeboid cells (devoid of any dendritic processes) in the majority of retinas in all experimental groups, but demonstrate no significant change in the average monocyte density across experimental groups ( Fig. 5 C).…”

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

“…Indeed, previous studies have shown that under certain conditions (e.g. in an empty microglial niche) induced by microglial depletion, peripheral myeloid cells can infiltrate and serve as the source for microglial repopulation in the brain parenchyma [40][41][42][43] . Thus, we reasoned that repopulation could be occurring from peripheral sources and undertook several complementary experimental approaches to explore this.…”