[Seminar]"Inflammation and Fibrosis in Pericyte-Deficient Retina" by Prof.Akiyoshi Uemur_Nagoya City University Graduate School of Medical Sciencesa

Prof. Akiyoshi Uemura

-Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences

-Uemura Eye Clinic

[Abstract]

In retina, vascular endothelial cells and pericytes cooperatively establish blood-retina barrier (BRB), which is disrupted by dropout of pericytes in diabetic retinopathy (DR). In the advanced form of DR, formation of fibrovascular membranes causes blinding conditions including massive hemorrhage and retinal detachment. Although macrophages are implicated in the BRB breakdown and fibrosis, their specific roles remain elusive. Here I show that distinct macrophage subpopulations differentially contribute to the disease progression in pericyte-deficient retina. In postnatal mice, injections of an anti-PDGFRb antibody inhibited pericyte recruitment to developing retinal vessels, evoking inflammatory responses in endothelial and perivascular infiltration of pro-permeable macrophages (Uemura et al. J Clin Invest. 2002; Ogura et al. JCI Insight 2017).　After the onset of leakage-induced retinal detachment, macrophages migrated toward the apoptotic neurons in the deep retinal area, which subsequently initiated subretinal fibrosis. Fate mapping analyses and single-cell RNAseq analyses showed that these pro-fibrotic macrophages were M2-polarized microglia with high expression of CD206. Administration of a new CD206-targeting small molecule significantly suppressed subretinal fibrosis via macrophage reprogramming. These results suggest anti-fibrotic potency of CD206-targeting therapy for the treatment of DR as well as other eye diseases such as age-related macular degeneration.