Abstract TP567: Identification of Il-17/Cxcl5 as a Novel Regulator of Endothelial-Oligodendrocyte Signaling in Ischemic White Matter Disease

Abstract

Introduction: Cardiovascular risk factors including obesity accelerate the rate of ischemic white matter lesions through unknown mechanisms. Disruption of the normal signaling between endothelial cells and oligodendrocytes may drive the acceleration of white matter lesions. Here, we performed gain and loss of function studies of the IL-17/CXCL5 signaling cascade in white matter endothelia and determined the effect on oligodendrocytes. Methods: Obesity-induced activation of IL-17 receptor b was blocked using function-blocking anti-IL-17B antibodies injected systemically q3d for 6 weeks. Over-expression of CXCL5 in white matter endothelia was achieved using FLEX lentiviral administration in Tie2-Cre:tdTomato transgenic mice. Endothelial CXCL5 levels, oligodendrocyte number, and maturation were determined using 3D confocal microscopy. Focal white matter ischemic stroke was induced using stereotactic injection of the irreversible eNOS inhibitor L-Nio. Results: IL-17Rb and CXCL5 levels are significantly increased at RNA and protein levels in white matter endothelial cells in obese mice. Endothelial expression of CXCL5 is further increased after focal white matter stroke. Administration of function-blocking anti-IL-17B antibodies to high fat diet mice reduced the level of endothelial CXCL5 by 60.4% without changing endothelial IL-17Rb levels. The total number and mean distance of vessel-associated oligodendrocyte precursor cells (OPCs) was not different in control vs. anti-IL-17B treated animals. In normal weight Tie2-Cre:tdTomato mice, forced over-expression of CXCL5 resulted in an increased number of vessel-associated OPCs compared to control. In obese mice, stroke-responsive OPCs are increased 37% at 7d after focal white matter stroke and remyelination of focal white matter lesions at 28d is impaired. Conclusions: Chronic cardiovascular risk factors such as obesity promote changes in white matter endothelia including activation of IL-17/CXCL5 signaling. Up-regulation of CXCL5 in white matter endothelia attracts OPCs to vessels and exaggerates the injury response to focal white matter stroke. Endothelial-oligodendrocyte signaling may provide novel therapeutic targets for ischemic white matter disease.