The Role of CXCR3 in Neurological Diseases

Zhou, Ya-Qun; Liu, Dai-Qiang; Chen, Shu-Ping; Sun, Jia; Zhou, Xue-Rong; Xing, Cui; Ye, Da-Wei; Tian, Yu-Ke

Multiple sclerosis (MS), also known as disseminated sclerosis, is a chronic inflammatory disease of the CNS which is characterized by destruction of myelin and oligodendrocytes in the brain and spinal cord [35, 36] . Mounting evidence has suggested that CXCR3 plays a vital part in MS. Balashov et al. [21] first reported that CXCR3 positive T cells were increased in blood of relapsing/remitting and progressive MS compared with controls. They also found that CXCL10, one of the CXCR3 ligands, was expressed by astrocytes in MS brain lesions but not unaffected white matter of control or MS subjects. These results suggested that CXCL10/CXCR3 expression level may be used for immunologic staging of MS and provided a rationale for the use of agents blocking CXCR3 as a therapeutic approach in the treatment of MS. Using immunocytochemistry, Simpson et al. [37] confirmed the expression of CXCL9 and CXCL10, and their receptor CXCR3 in post-mortem CNS tissue from MS cases at different stages of lesion development. Their results showed that both macrophages and astrocytes were active in demyelinating lesions predominantly expressed CXCL9 and CXCL10, and CXCR3 was expressed by T cells and by astrocytes within the plaque. The differential expression of chemokines indicated that blocking chemokine receptors may serve as an anti-inflammatory therapy for MS. On the other hand, CXCL10 and CXCR3 were significantly increased in the CSF of patients with MS compared with controls [38] [39] [40] . Moreover, the increased level of CXCL10 was associated with clinical relapses in MS. Compared with secondary progressive MS, the concentration of CXCL10 was significantly greater in patients with relapsing/remitting, which was correlated significantly with CXCR3 expression on CSF CD4 + T cells from patients with MS. In another study, Sindern et al. [41] demonstrated that the increased level of CXCR3 positive T-cells in the CSF was strongly associated with active MRI lesion appearance in patients with relapsing/remitting MS, which might be the result of migration of activated T-cells from the circulation into the CSF. Consistent with previous reports, this study confirmed the hypothesis that CXCR3 might be involved in the development of acute MS lesions, leading to therapeutic intervention via blocking CXCR3. By analyzing the expression of CXCR3 on peripheral lymphocytes in 18 MS patients, Mahad et al. [42] found that the increased expression of CXCR3 on peripheral blood CD4 + lymphocytes was associated with all relapses and that the fluctuations of CXCR3 expression was significantly greater in patients with MS than controls. This study provided further evidence for the potential therapeutic value of CXCR3 antagonists. The therapeutic effect of IFN-β on patients with MS is well established [43] [44] [45] . After treatment with IFN-β for three months, Sorensen et al. [46] found that the expression of CXCR3 on CD4 + and CD8 + T cells was significantly reduced, whereas the expression of other receptors (e.g. CCR1, CCR2, CCR3, CCR5) was unaltered. This results indicated that IFN-β may exert its therapeutic effect on MS patients by suppressing the expression of CXCR3.