IL-17/CXCL5 signaling within the oligovascular niche mediates human and mouse white matter injury

Cerebral small vessel disease and brain white matter injury are worsened by cardiovascular risk factors including obesity. Molecular pathways in cerebral endothelial cells activated by chronic cerebrovascular risk factors alter cell-cell signaling, blocking endogenous and post-ischemic white matter repair. Using cell-specific translating ribosome affinity purification (RiboTag) in white matter endothelia and oligodendrocyte progenitor cells (OPCs), we identify a coordinated interleukin-chemokine signaling cascade within the oligovascular niche of subcortical white matter that is triggered by diet-induced obesity (DIO). DIO induces interleukin-17B (IL-17B) signaling that acts on the cerebral endothelia through IL-17Rb to increase both circulating and local endothelial expression of CXCL5. In white matter endothelia, CXCL5 promotes the association of OPCs with the vasculature and triggers OPC gene expression programs regulating cell migration through chemokine signaling. Targeted blockade of IL-17B reduced vessel-associated OPCs by reducing endothelial CXCL5 expression. In multiple human cohorts, blood levels of CXCL5 function as a diagnostic and prognostic biomarker of vascular cognitive impairment.

Automated summary

Cardiovascular risk factors including obesity worsen cerebral small vessel disease and brain white matter injury. Chronic cerebrovascular risk factors activate molecular pathways in cerebral endothelial cells that alter cell-cell signaling, blocking endogenous and post-ischemic white matter repair. Using cell-specific translating ribosome affinity purification (RiboTag), a coordinated interleukin-chemokine signaling cascade is identified within the oligovascular niche of subcortical white matter triggered by diet-induced obesity (DIO). DIO induces interleukin-17B (IL-17B) signaling, which acts on cerebral endothelial cells through IL-17Rb, increasing both circulating and local endothelial expression of CXCL5. In white matter endothelia, CXCL5 promotes the association of oligodendrocyte progenitor cells (OPCs) with the vasculature and triggers OPC gene expression programs regulating cell migration through chemokine signaling. Targeted blockade of IL-17B reduces vessel-associated OPCs by reducing endothelial CXCL5 expression. CXCL5 blood levels serve as diagnostic and prognostic biomarkers of vascular cognitive impairment in multiple human cohorts.