Infiltrating monocyte-derived macrophages promote neurovascular remodeling after retinal ischemia/reperfusion injury

Ischemic retinopathies, including diabetic retinopathy and retinal vein occlusion, are major causes of irreversible vision loss worldwide. Although infiltrating monocyte-derived macrophages (MDMs) are commonly viewed as drivers of post-ischemic inflammation, their stage-specific contribution to endogenous retinal repair remains unclear. Using the mouse retinal ischemia–reperfusion (RI/R) injury model, we performed longitudinal transcriptomic profiling to characterize transcriptional alterations in infiltrating MDMs. We further developed clodronate liposome (CL)-mediated monocyte/macrophage depletion and bone marrow‑derived macrophage (BMDM) reconstitution to dissect the functional contributions of infiltrating MDMs following RI/R injury. The temporal pattern of MDM infiltration paralleled both neurovascular injury and subsequent repair following RI/R injury. Longitudinal transcriptomic analyses revealed that infiltrating MDMs retained a transcriptional program associated with neurovascular remodeling during their residence in the injured retina. CL-mediated monocyte/macrophage depletion compromised blood–retinal barrier (BRB) restoration and tissue repair after RI/R injury, while exacerbating retinal ganglion cell (RGC) loss and visual dysfunction. BMDM reconstitution rescued the defective retinal neurovascular remodeling caused by monocyte/macrophage depletion. Upstream regulator analysis identified TREM2 and MAFB as candidate regulators governing transcriptional reprogramming in retinal-infiltrating MDMs. Stimulation of BMDMs with the TREM2 agonistic antibody 4D9 upregulated molecules related to neurovascular remodeling and enhanced BMDM phagocytic capacity. Moreover, conditioned medium derived from 4D9-activated BMDMs partially restored ZO-1 protein levels in bEnd.3 endothelial cells exposed to oxygen-glucose deprivation/reperfusion (OGD/R) injury. Importantly, the pro-repair phenotype of BMDMs induced by TREM2 activation was attenuated by MAFB knockdown. These findings support a previously underappreciated reparative role of MDMs in neurovascular remodeling after RI/R injury. Therapeutic strategies aimed at selectively enhancing or reprogramming the reparative activity of MDMs may offer a promising approach for the treatment of ischemic retinopathies.