SDF1-CXCR4 Signaling Maintains Central Post-Stroke Pain through Mediation of Glial-Neuronal Interactions.

Fei Yang,Chun-Li Li,Na Wei,Wen-Jun Luo,Fan Yang,Wei Sun,Yan Wang,Su-Min Guan,Jiang-Lin Wang,Jun Chen,Xiao-Liang Wang

doi:10.3389/fnmol.2017.00226

Abstract

Central post-stroke pain (CPSP) is an intractable central neuropathic pain that has been poorly studied mechanistically. Here we showed that stromal cell-derived factor 1 (SDF1 or CXCL12), a member of the CXC chemokine family, and its receptor CXCR4 played a key role in the development and maintenance of thalamic hemorrhagic CPSP through hypoxia inducible factor 1α (HIF-1α) mediated microglial-astrocytic-neuronal interactions. First, both intra-thalamic collagenase (ITC) and SDF1 injections could induce CPSP that was blockable and reversible by intra-thalamic administration of both AMD3100 (a selective CXCR4 antagonist) and inhibitors of microglial or astrocytic activation. Second, long-term increased-expression of SDF1 and CXCR4 that was accompanied by activations of both microglia and astrocytes following ITC could be blocked by both AMD-3100 and YC-1, a selective inhibitor of HIF-1α. AMD-3100 could also inhibit release of proinflammatory mediators (TNFα, IL1β and IL-6). Increased-expression of HIF-1α, SDF1, CXCR4, Iba1 and GFAP proteins could be induced by both ITC and intra-thalamic CoCl2, an inducer of HIF-1α that was blockable by both HIF-1α inhibition and CXCR4 antagonism. Finally, inhibition of HIF-1α was only effective in prevention, but not in treatment of ITC-induced CPSP. Taken together, the present study demonstrated that in the initial process of thalamic hemorrhagic state HIF-1α up-regulated SDF1-CXCR4 signaling, while in the late process SDF1-CXCR4 signaling-mediated positive feedback plays more important role in glial-glial and glial-neuronal interactions and might be a novel promising molecular target for treatment of CPSP in clinic.

Highlights

Stroke is the leading cause of adult disability worldwide (Feigin et al, 2014)
The present study demonstrated that intra-thalamic collagenase (ITC)-induced Central post-stroke pain (CPSP) hypersensitivity was initiated by microglial-astrocytic-neuronal interactions in the peri-lesion sites through hypoxia inducible factor 1α (HIF-1α)-dependent up-regulation of SDF1-CXCR4 signaling in microglia, astrocytes and neurons at the early stage, while it was maintained by persistent release of pro-inflammatory mediators (TNFα, IL-1β and IL-6) through SDF1-CXCR4 signaling-mediated glial-glial and glial-neuronal positive feedback regulation at the late stage
We found that the protein level of HIF-1α was significantly increased at the early phase, but not in the late phase, after hemorrhagic stroke induced by ITC

Summary

Introduction

Stroke is the leading cause of adult disability worldwide (Feigin et al, 2014) In both developed countries and high income developing countries such as China, acute treatment of stroke has been improved substantially, resulting in decrease in mortality and increase in the proportion of survivors with disability (Feigin et al, 2014; Yang et al, 2014; Ferro et al, 2016; Yang Y. et al, 2016). In a critical review on the animal models for CPSP, the experimental thalamic hemorrhage model induced by intrathalamic collagenase (ITC) injection (Wasserman and Koeberle, 2009; Yang et al, 2014; Kuan et al, 2015; Yang Y. et al, 2016) was believed to be the only one with relatively high reproducibility (De Vloo et al, 2017)

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Conclusion