CXCR3 determines strain susceptibility to murine cerebral malaria by mediating T lymphocyte migration toward IFN-gamma-induced chemokines.
Cerebral malaria (CM) results from the binding of infected erythrocytes and leukocytes to brain endothelia. The precise mechanisms underlying lymphocyte recruitment and activation in CM remain unclear. Therefore, the expression of various chemokines was quantified in brains of mice infected with Plasmodium berghei ANKA (PbA). Several chemokines attracting monocytes and activated T-lymphocytes were expressed at high levels. Their expression was almost completely abrogated in IFN-gamma ligand and receptor KO mice, indicating that IFN-gamma is an essential chemokine inducer in vivo. Surprisingly, the expression levels of chemokines, IFN-gamma and also adhesion molecules in the brain were not lower in CM-resistant Balb/c and DBA/2 mice compared to CM-sensitive C57BL/6 and DBA/1 mice, although T lymphocyte sequestration in the brain was significantly less in CM-resistant than in CM-sensitive mice. This difference correlated with a higher up-regulation of the CXC chemokine receptor (CXCR)-3 on splenic T cells and a higher chemotactic response to IFN-gamma-inducible protein-10 (IP-10) in C57BL/6 compared to Balb/c mice. In conclusion, parasite-induced IFN-gamma in the brain results in high local expression levels of specific chemokines for monocytes and lymphocytes. The strain-dependent susceptibility to develop CM is more related to the expression of CXCR3 in circulating leukocytes than to the chemokine expression levels in the brain.
Van den Steen
Philippe E
PE
Laboratory of Immunobiology, Rega Institute for Medical Research, Catholic University of Leuven, Leuven, Belgium. philippe.vandensteen@rega.kuleuven.be
Deroost
Katrien
K
Van Aelst
Ilse
I
Geurts
Nathalie
N
Martens
Erik
E
Struyf
Sofie
S
Nie
Catherine Q
CQ
Hansen
Diana S
DS
Matthys
Patrick
P
Van Damme
Jo
J
Opdenakker
Ghislain
G
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology; D054427:Chemokine CXCL6 / Q000235:genetics / Q000276:immunology; D018925:Chemokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D016779:Malaria, Cerebral / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D010962:Plasmodium berghei / Q000276:immunology; D054367:Receptors, CXCR3 / Q000276:immunology*; D017471:Receptors, Interferon / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D015996:Survival Rate; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D000096743:Interferon gamma Receptor
D015815:Cell Adhesion Molecules; D054377:Chemokine CXCL12; D054427:Chemokine CXCL6; D018925:Chemokines; D007371:Interferon-gamma; D008024:Ligands; D054367:Receptors, CXCR3; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C515188:Cxcr3 protein, mouse