CXCL10 stabilizes T cell-brain endothelial cell adhesion leading to the induction of cerebral malaria.
Malaria remains one of the world's most significant human infectious diseases and cerebral malaria (CM) is its most deadly complication. CM pathogenesis remains incompletely understood, hindering the development of therapeutics to prevent this lethal complication. Elevated levels of the chemokine CXCL10 are a biomarker for CM, and CXCL10 and its receptor CXCR3 are required for experimental CM (ECM) in mice, but their role has remained unclear. Using multiphoton intravital microscopy, CXCR3 receptor- and ligand-deficient mice and bone marrow chimeric mice, we demonstrate a key role for endothelial cell-produced CXCL10 in inducing the firm adhesion of T cells and preventing their cell detachment from the brain vasculature. Using a CXCL9 and CXCL10 dual-CXCR3-ligand reporter mouse, we found that CXCL10 was strongly induced in the brain endothelium as early as 4 days after infection, while CXCL9 and CXCL10 expression was found in inflammatory monocytes and monocyte-derived DCs within the blood vasculature on day 8. The induction of both CXCL9 and CXCL10 was completely dependent on IFN-γ receptor signaling. These data demonstrate that IFN-γ-induced, endothelium-derived CXCL10 plays a critical role in mediating the T cell-endothelial cell adhesive events that initiate the inflammatory cascade that injures the endothelium and induces the development of ECM.
['Sorensen|Elizabeth W|EW|', 'Lian|Jeffrey|J|', 'Ozga|Aleksandra J|AJ|', 'Miyabe|Yoshishige|Y|', 'Ji|Sophina W|SW|', 'Bromley|Shannon K|SK|', 'Mempel|Thorsten R|TR|', 'Luster|Andrew D|AD|']
D000818:Animals D001921:Brain D002448:Cell Adhesion D054357:Chemokine CXCL10 D054370:Chemokine CXCL9 D042783:Endothelial Cells D005260:Female D008024:Ligands D016779:Malaria, Cerebral D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D009000:Monocytes D054367:Receptors, CXCR3 D017471:Receptors, Interferon D015398:Signal Transduction D013601:T-Lymphocytes
Infectious disease Chemokines Cell migration/adhesion Immunology Neuroimaging