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Inhibition of stromal cell–derived factor-1α/CXCR4 signaling restores the blood-retina barrier in pericyte-deficient mouse retinas
Keisuke Omori, … , Akiyoshi Uemura, Takahisa Murata
Keisuke Omori, … , Akiyoshi Uemura, Takahisa Murata
Published December 6, 2018
Citation Information: JCI Insight. 2018;3(23):e120706. https://doi.org/10.1172/jci.insight.120706.
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Research Article Inflammation Ophthalmology

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

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Abstract

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-1α (SDF-1α) 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 SDF-1α. 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-1α 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 SDF-1α/CXCR4 signaling pathway may be a potential therapeutic target in DR.

Authors

Keisuke Omori, Nanae Nagata, Kaori Kurata, Yoko Fukushima, Erika Sekihachi, Nobutaka Fujii, Tomoko Namba-Hamano, Yoshitsugu Takabatake, Marcus Fruttiger, Takashi Nagasawa, Akiyoshi Uemura, Takahisa Murata

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Figure 1

SDF-1α/CXCR4 expression was observed in retinal ECs in APB5-treated mouse retina.

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SDF-1α/CXCR4 expression was observed in retinal ECs in APB5-treated mous...
(A) The effect of APB5 on Sdf1a mRNA expression in P5, P7, and P9 mouse retinas (n = 6). (B) Representative images of retina in situ hybridization of Sdf1a (purple) and collagen IV (brown) on P8. White arrowheads indicate a double-positive staining region of Sdf1a and collagen IV. Scale bar: 50 μm. (C) Representative images of P8 mouse flow cytometry. Pink circles in left 2 graphs indicate CD11b+CD45hi macrophages. Pink rectangles in right 2 graphs indicate CXCR4-positive macrophages. (D) Representative images of P8 mouse flow cytometry. Pink rectangles in left 2 graphs indicate CD31+CD45– ECs. Pink rectangles in 2 right graphs indicate CXCR4-positive ECs. Significantly different from the results in vehicle-treated mice at *P < 0.05, significantly different from the results in vehicle-treated mice.

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