A role for a CXCR2/phosphatidylinositol 3-kinase gamma signaling axis in acute and chronic vascular permeability.
Most proangiogenic polypeptide growth factors and chemokines enhance vascular permeability, including vascular endothelial growth factor (VEGF), the main target for anti-angiogenic-based therapies, and interleukin-8 (IL-8), a potent proinflammatory mediator. Here, we show that in endothelial cells IL-8 initiates a signaling route that converges with that deployed by VEGF at the level of the small GTPase Rac1 and that both act through the p21-activated kinase to promote the phosphorylation and internalization of VE-cadherin. However, whereas VEGF activates Rac1 through Src-related kinases, IL-8 specifically signals to Rac1 through its cognate G protein-linked receptor, CXCR2, and the stimulation of the phosphatidylinositol 3-kinase gamma (PI3Kgamma) catalytic isoform, thereby providing a specific molecular targeted intervention in vascular permeability. These results prompted us to investigate the potential role of IL-8 signaling in a mouse model for retinal vascular hyperpermeability. Importantly, we observed that IL-8 is upregulated upon laser-induced retinal damage, which recapitulates enhanced vascularization, leakage, and inflammatory responses. Moreover, blockade of CXCR2 and PI3Kgamma was able to limit neovascularization and choroidal edema, as well as macrophage infiltration, therefore contributing to reduce retinal damage. These findings indicate that the CXCR2 and PI3Kgamma signaling pathway may represent a suitable target for the development of novel therapeutic strategies for human diseases characterized by vascular leakage.
Gavard
Julie
J
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA. julie.gavard@inserm.fr
Hou
Xu
X
Qu
Yi
Y
Masedunskas
Andrius
A
Martin
Daniel
D
Weigert
Roberto
R
Li
Xuri
X
Gutkind
J Silvio
JS
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability; D002460:Cell Line; D058544:Class Ib Phosphatidylinositol 3-Kinase; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007834:Lasers / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D058544:Class Ib Phosphatidylinositol 3-Kinase; D016209:Interleukin-8; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D023063:Receptors, Interleukin-8B; D042461:Vascular Endothelial Growth Factor A; D020830:rac1 GTP-Binding Protein; D000099152:Cadherin 5; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse