CXCL10 stabilizes T cell–brain endothelial cell adhesion leading to the induction of cerebral malaria
Elizabeth W. Sorensen, Jeffrey Lian, Aleksandra J. Ozga, Yoshishige Miyabe, Sophina W. Ji, Shannon K. Bromley, Thorsten R. Mempel, Andrew D. Luster
Elizabeth W. Sorensen, Jeffrey Lian, Aleksandra J. Ozga, Yoshishige Miyabe, Sophina W. Ji, Shannon K. Bromley, Thorsten R. Mempel, Andrew D. Luster
View: Text | PDF
Research Article Immunology Infectious disease

CXCL10 stabilizes T cell–brain endothelial cell adhesion leading to the induction of cerebral malaria

Abstract

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.

Authors

Elizabeth W. Sorensen, Jeffrey Lian, Aleksandra J. Ozga, Yoshishige Miyabe, Sophina W. Ji, Shannon K. Bromley, Thorsten R. Mempel, Andrew D. Luster

×

Figure 6

CXCL9 and CXCL10 induction is dependent on IFN-γR.

Options: View larger image (or click on image) Download as PowerPoint
CXCL9 and CXCL10 induction is dependent on IFN-γR. (A) REX3-Ifnar–/– (IF...
(A) REX3-Ifnar–/– (IFNAR–/–, top row) and REX3-Ifngr–/– (IFNγR–/–, bottom row) were infected with Plasmodium berghei ANKA (PbA) and brain cortices were analyzed by whole-mount immunofluorescence on day 8 post-infection (p.i.). Representative images are shown stained with anti-CD31-AF488 (green) and anti-CD45-APC (white). CXCL9-RFP is red and CXCL10-BFP is blue. Scale bars: 50 μm. n = 6 mice/group total from 3 independent experiments. (B and C) qPCR analysis of CXCL9 and CXCL10 RNA levels relative to GAPDH in the (B) brains and (C) spleens of PbA-infected WT (black bars), Ifnar–/– (gray bars), and Ifngr–/– (black bars) mice on the indicated days p.i. The numbers of mice/group total from 3 independent experiments are listed in day order (i.e., day 0, 2, 4, 6, 8). Brain CXCL9: WT n = 9, 8, 12, 9, 10; Ifnar–/– n = 9, 9, 9, 8, 10; Ifngr–/– n = 9, 9, 11, 9, 11. Brain CXCL10: WT n = 9, 8, 12, 9, 10; Ifnar–/– n = 9, 9, 9, 9, 10, Ifngr–/– n = 9, 9, 9, 11, 11. Spleen CXCL9: WT n = 5, 10, 9, 9, 9; Ifnar–/– n = 9, 9, 6, 9, 7; Ifngr–/– n = 9, 9, 9, 9, 14. Spleen CXCL10: WT n = 9, 10, 9, 9, 9; Ifnar–/– n = 9, 9, 6, 9, 5; Ifngr–/– n = 9, 9, 9, 11, 11. The groups in B–D were compared using 2-way ANOVA with Bonferroni’s multiple comparison test. Bars represent the mean with SEM in all plots.