Severe disease, unaltered leukocyte migration, and reduced IFN-gamma production in CXCR3-/- mice with experimental autoimmune encephalomyelitis.
Experimental autoimmune encephalomyelitis (EAE) is a CD4(+) Th1 T cell-mediated disease of the CNS, used to study certain aspects of multiple sclerosis. CXCR3, the receptor for CXCL10, CXCL9, and CXCL11, is preferentially expressed on activated Th1 T cells and has been proposed to govern the migration of lymphocytes into the inflamed CNS during multiple sclerosis and EAE. Unexpectedly, CXCL10-deficient mice were susceptible to EAE, leaving uncertain what the role of CXCR3 and its ligands might play in this disease model. In this study, we report that CXCR3(-/-) mice exhibit exaggerated severity of EAE compared with wild-type (CXCR3(+/+)) littermate mice. Surprisingly, there were neither quantitative nor qualitative differences in CNS-infiltrating leukocytes between CXCR3(+/+) and CXCR3(-/-) mice with EAE. Despite these equivalent inflammatory infiltrates, CNS tissues from CXCR3(-/-) mice with EAE showed worsened blood-brain barrier disruption and more von Willebrand factor-immunoreactive vessels within inflamed spinal cords, as compared with CXCR3(+/+) mice. Spinal cords of CXCR3(-/-) mice with EAE demonstrated decreased levels of IFN-gamma, associated with reduced inducible NO synthase immunoreactivity, and lymph node T cells from CXCR3(-/-) mice primed with MOG(35-55) secreted less IFN-gamma in Ag-driven recall responses than cells from CXCR3(+/+) animals. CXCR3(-/-) lymph node T cells also showed enhanced Ag-driven proliferation, which was reduced by addition of IFN-gamma. Taken with prior findings, our data show that CXCL10 is the most relevant ligand for CXCR3 in EAE. CXCR3 does not govern leukocyte trafficking in EAE but modulates T cell IFN-gamma production and downstream events that affect disease severity.
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, OH 44195, USA.
Liping
L
Liu
Deren
D
Huang
Masaru
M
Matsui
Toby T
TT
He
Taofang
T
Hu
Julie
J
Demartino
Bao
B
Lu
Craig
C
Gerard
Richard M
RM
Ransohoff
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006023:Glycoproteins / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018991:Myelin Proteolipid Protein / Q000494:pharmacology; D063308:Myelin-Oligodendrocyte Glycoprotein; D052247:Nitric Oxide Synthase Type II / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010539:Permeability; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000172:deficiency* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
D000906:Antibodies; C515188:Cxcr3 protein, mouse; D006023:Glycoproteins; D018991:Myelin Proteolipid Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; C445081:myelin oligodendrocyte glycoprotein (35-55); C435023:myelin proteolipid protein (139-151); D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II