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

Pain plays a vital role in protecting us against damaging stimuli [74] [75] [76] . However, chronic pain presents a major challenge due to its complex natural history, unclear etiology, and poor response to therapy [77] [78] [79] . There is compelling evidence supporting the involvement of neuroinflammation in chronic pain [80] [81] [82] [83] [84] . Our lab has been investigating the mechanisms of chronic pain for decades [85] [86] [87] [88] [89] [90] [91] . Previously, we have shown the involvement of CXCL10/CXCR3 signaling in BCP rat models [23, 92] . After intra-tibial inoculation of Walker 256 mammary gland carcinoma cells, the BCP model was established, indicated by downregulation of paw withdrawal threshold (PWT) and bone destruction. Our real-time polymerase chain reaction (PCR) and immunohistochemical analyses showed that both CXCL10 and its receptor CXCR3 were up-regulated in the spinal cord of BCP rats. Blocking the CXCL10/CXCR3 signaling via anti-CXCL10 antibody or CXCR3 antagonist AMG487 prevented the development of BCP and microglial activation. Moreover, inhibiting microglial activation attenuated CXCL10 upregulation in BCP rats. These results suggested that CXCL10/CXCR3 signaling participated in BCP via activation of microglia in rat models. Our further study revealed the cellular mechanism of how CXCR3 mediated BCP [25] . We confirmed that CXCR3 was significantly increased in the spinal cord of BCP rats and co-localized with either neurons, microglia, and astrocytes in the spinal cord, or non-peptidergic-, peptidergic-, and A-type neurons in the dorsal root ganglion (DRG). Moreover, spinal phosphorylation of Akt and extracellular signal-regulated kinase (ERK1/2) were markedly upregulated in BCP rats in a timedependent manner. Meanwhile, CXCR3 was co-localized with either pAkt or pERK1/2. Blockage of either Akt or ERK1/2 attenuated the mechanical allodynia in BCP rats. Furthermore, CXCR3 antagonist AMG487 suppressed the upregulation of pAkt and pERK1/2. Taken together, these results indicated that the activation of spinal chemokine receptor CXCR3 mediated BCP through Akt-ERK pathway. A very recent study performed by Jiang et al. confirmed the pivotal role of CXCR3 in neuropathic pain [93] . They found that the expression of CXCR3 was significantly upregulated mainly in the spinal neuron following spinal nerve ligation (SNL). Moreover, CXCL10, a ligand of CXCR3, was also considerably increased in the spinal neurons and astrocytes in SNL mice. Additionally, inhibiting the expression of CXCR3 by CXCR3-/-mice and shRNA targeting the sequence of mice Cxcr3 as well as CXCR3 antagonist NBI-74330 attenuated SNL-induced mechanical allodynia and thermal hyperalgesia. More importantly, they revealed the epigenetic mechanism of how CXCR3 contributed to neuro-pathic pain. These results suggested that targeting CXCR3 may alleviated the established choric pain and novel CXCR3 antagonist with fewer side effects should be developed.