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

Experimental autoimmune encephalomyelitis (EAE), a rodent model of human MS, is a CD4 + Th1 cell-and Th17 cell-mediated demyelinating disease of the CNS [47] . The role of CXCR3 in EAE has been widely studied. Considering that CXCR3 and its ligands are elevated in MS patients, it was proposed that blocking CXCR3 or neutralization of its ligands would inhibit the development of EAE. However, Narumi et al. [48] reported that EAE rats treated with monoclonal antibody (mAb) against CXCL10 exacerbated the disease scores with less enlarged draining lymph nodes than treated with control mAb. The smaller draining lymph nodes in EAE rats treated with anti-CXCL10 mAb might be explained by the following mechanism: neutralization of CXCL10 causes an increased release of Th1 cells from lymph nodes, which results in increased migration to the CNS where CXCL11, another ligand for CXCR3, is induced as well. Moreover, CXCL10-deficient mice exhibited a reduced threshold for EAE induction and developed severe EAE after immunization with low doses of myelin oligodendroglial glycoprotein (MOG)p33-55 that produced minimal disease in wild-type littermates [49] . In another study, Muller et al. examined the function of CXCR3 signaling in EAE using CXCR3 deficient (CXCR3 _ / _ ) mice [50, 51] . No significant difference was found in terms of time to onset and peak disease severity in CXCR3 _ / _ and wild-type (WT) mice. However, CXCR3 _ / _ mice had more severe chronic disease with increased demyelination and axonal damage. Additionally, the inflammatory lesions were more widespread throughout the CNS in CXCR3 _ / _ mice than WT mice in which inflammatory lesions consisted of well-demarcated perivascular mononuclear cell infiltrates. Furthermore, Foxp3 + regulatory T cells were significantly reduced in number and were scattered in the spinal cord of CXCR3 _ / _ mice. These results suggested that CXCR3 signaling plays a major protective role in EAE by constraining CD4 + T cells to the perivascular space in the CNS, promoting regulatory T cell accumulation and facilitating interaction of these cells with effector T cells, thus limiting autoimmune-mediated tissue damage. In a mouse model of neurotropic coronavirusinduced encephalomyelitis, Marques et al. [52] found that the accumulation of antibody secreting cells (ASC) in the CNS was mediated by CXCR3. In CXCR3 _ / _ mice, both the total and virus-specific ASC were reduced greater than 80%. Furthermore, neither virus-specific ASC trafficking to bone marrow nor antiviral serum antibody was reduced relative to levels in control mice. Additionally, infected CXCR3 _ / _ mice showed elevated levels of persisting viral RNA, sustained infectious virus, increased clinical disease and mortality. These results indicated that CXCR3 played a vital role in the recruitment of activated ASC into the inflamed CNS and highlighted its protective role during persistent infection. A further study demonstrated that CXCL10 is critical for the recruitment of ASC to the CNS vasculature and ASC entry into the CNS parenchyma in a mouse model of viral encephalomyelitis [53] . In this study, they found reduced CNS IgG and κ-light chain mRNA and virus-specific Ab as well as impaired ASC recruitment in CXCL10 _ / _ rather than CXCL9 _ / _ mice. Moreover, the ASC recruited to the CNS in CXCL10 _ / _ mice restricted to the vasculature, whereas it was localized in the parenchyma in wild-type and CXCL9 _ / _ mice. Recently, the CXCR3-CXCL10 axis