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

Omori, K; Nagata, N; Kurata, K; Fukushima, Y; Sekihachi, E; Fujii, N; Namba-Hamano, T; ... Murata, T; + view all (2018) Inhibition of stromal cell-derived factor-1α/CXCR4 signaling restores the blood-retina barrier in pericyte-deficient mouse retinas. JCI Insight , 3 (23) 10.1172/jci.insight.120706. Green open access

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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.

Type: Article
Title: Inhibition of stromal cell-derived factor-1α/CXCR4 signaling restores the blood-retina barrier in pericyte-deficient mouse retinas
Open access status: An open access version is available from UCL Discovery
DOI: 10.1172/jci.insight.120706
Additional information: This version is the version of the record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Chemokines, Inflammation, Macrophages, Ophthalmology, endothelial cells
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10065148
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