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Severe disease, unaltered leukocyte migration, and reduced IFN-gamma production in CXCR3-/- mice with experimental autoimmune encephalomyelitis.
J Immunol. 2006 Apr 01; 176(7):4399-409.JI

Abstract

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.

Authors+Show Affiliations

Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, OH 44195, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16547278

Citation

Liu, Liping, et al. "Severe Disease, Unaltered Leukocyte Migration, and Reduced IFN-gamma Production in CXCR3-/- Mice With Experimental Autoimmune Encephalomyelitis." Journal of Immunology (Baltimore, Md. : 1950), vol. 176, no. 7, 2006, pp. 4399-409.
Liu L, Huang D, Matsui M, et al. Severe disease, unaltered leukocyte migration, and reduced IFN-gamma production in CXCR3-/- mice with experimental autoimmune encephalomyelitis. J Immunol. 2006;176(7):4399-409.
Liu, L., Huang, D., Matsui, M., He, T. T., Hu, T., Demartino, J., Lu, B., Gerard, C., & Ransohoff, R. M. (2006). Severe disease, unaltered leukocyte migration, and reduced IFN-gamma production in CXCR3-/- mice with experimental autoimmune encephalomyelitis. Journal of Immunology (Baltimore, Md. : 1950), 176(7), 4399-409.
Liu L, et al. Severe Disease, Unaltered Leukocyte Migration, and Reduced IFN-gamma Production in CXCR3-/- Mice With Experimental Autoimmune Encephalomyelitis. J Immunol. 2006 Apr 1;176(7):4399-409. PubMed PMID: 16547278.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Severe disease, unaltered leukocyte migration, and reduced IFN-gamma production in CXCR3-/- mice with experimental autoimmune encephalomyelitis. AU - Liu,Liping, AU - Huang,Deren, AU - Matsui,Masaru, AU - He,Toby T, AU - Hu,Taofang, AU - Demartino,Julie, AU - Lu,Bao, AU - Gerard,Craig, AU - Ransohoff,Richard M, PY - 2006/3/21/pubmed PY - 2006/5/2/medline PY - 2006/3/21/entrez SP - 4399 EP - 409 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 176 IS - 7 N2 - 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. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/16547278/Severe_disease_unaltered_leukocyte_migration_and_reduced_IFN_gamma_production_in_CXCR3_/__mice_with_experimental_autoimmune_encephalomyelitis_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=16547278 DB - PRIME DP - Unbound Medicine ER -