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Inhibition of stromal cell-derived factor-1α/CXCR4 signaling restores the blood-retina barrier in pericyte-deficient mouse retinas.
- Source :
-
JCI insight [JCI Insight] 2018 Dec 06; Vol. 3 (23). Date of Electronic Publication: 2018 Dec 06. - Publication Year :
- 2018
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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.
- Subjects :
- Animals
Chemokine CXCL12 genetics
Chemokines
Cytokines metabolism
Diabetic Retinopathy therapy
Disease Progression
Endothelial Cells metabolism
Endothelial Cells pathology
Macrophages
Mice
Mice, Inbred C57BL
Receptors, CXCR4 genetics
Retina diagnostic imaging
Retina growth & development
Retina pathology
Retinal Vessels growth & development
Blood-Retinal Barrier metabolism
Chemokine CXCL12 metabolism
Diabetic Retinopathy metabolism
Pericytes metabolism
Receptors, CXCR4 metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 3
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 30518679
- Full Text :
- https://doi.org/10.1172/jci.insight.120706