Inhibition of stromal cell-derived factor-1 alpha/CXCR4 signaling restores the blood-retina barrier in pericyte-deficient mouse retinas

In diabetic retinopathy (DR), pericyte dropout from capillary walls is believed to cause the breakdown of the blood-retina barrier (BRB), which subsequently leads to vision-threatening retinal edema. While various proinflammatory cytokines and chemokines are upregulated in eyes with DR, their distinct contributions to disease progression remain elusive. Here, we evaluated roles of stromal cell-derived factor-1 alpha (SDF-1 alpha) and its receptor CXCR4 in the BRB breakdown initiated by pericyte deficiency. After inhibition of pericyte recruitment to developing retinal vessels in neonatal mice, endothelial cells (ECs) upregulated the expression of SOF-1 alpha. Administration of CXCR4 antagonists, or EC-specific disruption of the CXCR4 gene, similarly restored the BRB integrity, even in the absence of pericyte coverage. Furthermore, CXCR4 inhibition significantly decreased both the expression levels of proinflammatory genes (P < 0.05) and the infiltration of macrophages (P< 0.05) into pericyte-deficient retinas. Taken together, EC-derived SDF-1 alpha induced by pericyte deficiency exacerbated inflammation through CXCR4 in an autocrine or paracrine manner and thereby induced macrophage infiltration and BRB breakdown. These findings suggest that the SOF1 alpha/CXCR4 signaling pathway may be a potential therapeutic target in DR.