Intrinsic neuronal activation of CXCR4 in regulation of regeneration program of the primary sensory neurons
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| Year of publication | 2022 |
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| Description | Chemokine signaling was initially recognized to play a role in immune cell trafficking and recirculation that is also associated with modulation of cytoskeletal elements. Chemokine CXCL12/CXCR4 axis is involved to a broad spectrum of processes associated with development, degeneration and regeneration of the nervous system tissue. Therefore, we hypothesize that CXCR4 neuronal activation can be linked with regulation of regeneration program in the neurons of after their axotomy. To verify this hypothesis, we used our experimental model of pro-regenerative program triggered by indirect conditioning of the rat cervical dorsal root ganglion (DRG) neurons in response to unilateral sciatic nerve lesions (Dubový et al. 2019). We first investigated regulation of CXCL12 and CXCR4 proteins and mRNAs in the cervical and lumbar DRG 7 days after unilateral sciatic nerve compression or transection. To demonstrate an involvement of intrinsic neuronal activation of CXCR4 in triggering of pro-regenerative state of DRG neurons, we monitored neurite regeneration capacity of the cervical DRG neurons under an in vivo and in vitro condition. In addition, axon regeneration distal to the ulnar nerve (UN) crush was assessed after sciatic nerve lesions and CXCR4 inhibition by intrathecal application of AMD3100. Neurite outgrowth of the cervical DRG neurons cultivated in vitro was investigated after CXCL12 or AMD3100 treatment. Immunohistochemical and RT-PCR analysis revealed increased levels of CXCL12 and CXCR4 proteins and mRNAs bilaterally in both lumbar and cervical DRG neurons after sciatic nerve lesions. The length of SCG10 immunopositive axons distal to UN crush reached significantly longer distance after sciatic nerve lesions compared with controls. Intrathecal application of AMD3100 reduced protein levels of both CXCR4 and CXCL12 as well as the distance reached by the regenerated axons. The results of in vivo model were confirmed by in vitro experiments. These results indicate that intrinsic CXCL12/CXCR4 signaling is involved in initiation of pro-regenerative program in the DRG neurons to promote their axon regeneration after nerve injury. |
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