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
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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

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Figure 8

Stromally produced CXCL10 influences survival and T cell interaction with the brain vasculature in PbA-infected mice.

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Stromally produced CXCL10 influences survival and T cell interaction wit...
Lethally irradiated WT, Cxcr3–/–, Cxcl9–/–, and Cxcl10–/– mice were reconstituted with DPE-GFP or DPE-GFP Cxcr3–/– bone marrow, as indicated. Eight weeks following reconstitution, chimeric mice were infected with Plasmodium berghei ANKA (PbA). (A) Kaplan-Meier survival curve. The numbers of mice/group total from 3 independent experiments were as follows: DPE-GFP→WT = 13, DPE-GFP Cxcr3–/–→Cxcr3–/– mice = 11, DPE-GFP→Cxcl9–/– = 10, DPE-GFP→Cxcl10–/– = 14. (B–D) Brain multiphoton intravital microscopy (MP-IVM) of chimeric mice on day 8 or 9 after infection. (B) Number of T cell tracks per field of view (FOV) was analyzed using Imaris software and (C) arrest coefficient was calculated using MATLAB. Violin plots contain box plots that display the median, 25th and 75th percentiles, and whiskers that represent the 95% confidence interval (note the median of the DPE-GFP→Cxcl10–/– chimeras is 0). Numbers of new T cell attachment and detachment events were manually counted and the (D) percentage of newly attached T cells that subsequently detached were calculated. The numbers of mice/group total from 3 independent experiments were as follows: DPE-GFP→WT = 5, DPE-GFP Cxcr3–/–→Cxcr3–/– mice = 10, DPE-GFP→Cxcl9–/– = 5, DPE-GFP→Cxcl10–/– = 5. Numbers shown just below the violin plot in C represent the total number of T cells analyzed. Groups were compared using either (A) log-rank (Mantel-Cox) test or (B–D) Kruskal-Wallis with Dunn’s multiple comparison test. Bars represent the median in all plots. BM, bone marrow.