Related Experiment Video
Updated: Aug 16, 2025
Dissection and Isolation of Murine Glia from Multiple Central Nervous System Regions
Published on: June 4, 2020
IL-17/CXCL5 signaling within the oligovascular niche mediates human and mouse white matter injury
Guanxi Xiao1, Rosie Kumar1, Yutaro Komuro1
1Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Abstract:
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.
Insights
Diet-induced obesity disrupts brain repair by activating interleukin-17B (IL-17B) signaling, which impairs oligodendrocyte progenitor cells (OPCs). Blocking IL-17B may restore white matter repair and offers a biomarker for cognitive impairment.
Area of Science:
- Neuroscience
- Immunology
- Vascular Biology
Background:
- Cardiovascular risk factors, including obesity, exacerbate cerebral small vessel disease and white matter injury.
- Molecular pathways in cerebral endothelial cells are altered by chronic risk factors, hindering white matter repair.
Purpose of the Study:
- To investigate the molecular mechanisms by which diet-induced obesity (DIO) affects the oligovascular niche in subcortical white matter.
- To identify signaling pathways involved in impaired brain repair.
Main Methods:
- Utilized cell-specific translating ribosome affinity purification (RiboTag) in white matter endothelia and oligodendrocyte progenitor cells (OPCs).
- Investigated the role of interleukin-17B (IL-17B) and its receptor (IL-17Rb) in DIO.
- Assessed the impact of CXCL5 on OPCs and vascular interactions.
Main Results:
- DIO triggers a coordinated interleukin-chemokine signaling cascade in the white matter oligovascular niche.
- IL-17B signaling increases endothelial CXCL5 expression, promoting OPC-vasculature association and migration.
- Targeted blockade of IL-17B reduced vessel-associated OPCs by decreasing endothelial CXCL5.
Conclusions:
- Obesity-induced IL-17B signaling disrupts the white matter repair process by affecting OPCs via CXCL5.
- CXCL5 in blood serves as a diagnostic and prognostic biomarker for vascular cognitive impairment in human cohorts.
