title: Peripheral nerve injury alters blood-spinal cord barrier functional and molecular integrity through a selective inflammatory pathway.
abstract: Peripheral nerve lesion triggers alterations in the spinal microenvironment that contribute to the pathogenesis of neuropathic pain. While neurons and glia have been implicated in these functional changes, it remains largely underexplored whether the blood-spinal cord barrier (BSCB) is also involved. The BSCB is an important component in the CNS homeostasis, and compromised BSCB has been associated with different pathologies affecting the spinal cord. Here, we demonstrated that a remote injury on the peripheral nerve in rats triggered a leakage of the BSCB, which was independent of spinal microglial activation. The increase of BSCB permeability to different size tracers, such as Evans Blue and sodium fluorescein, was restricted to the lumbar spinal cord and prominent for at least 4 weeks after injury. The spinal inflammatory reaction triggered by nerve injury was a key player in modulating BSCB permeability. We identified MCP-1 as an endogenous trigger for the BSCB leakage. BSCB permeability can also be impaired by circulating IL-1β. In contrast, antiinflammatory cytokines TGF-β1 and IL-10 were able to shut down the openings of the BSCB following nerve injury. Peripheral nerve injury caused a decrease in tight junction and caveolae-associated proteins. Interestingly, ZO-1 and occludin, but not caveolin-1, were rescued by TGF-β1. Furthermore, our data provide direct evidence that disrupted BSCB following nerve injury contributed to the influx of inflammatory mediators and the recruitment of spinal blood borne monocytes/macrophages, which played a major role in the development of neuropathic pain. These findings highlight the importance of inflammation in BSCB integrity and in spinal cord homeostasis.
authors.affiliation: The Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 2B2, Canada.
authors.forename: Stefania
authors.initials: S
authors.lastname: Echeverry
authors.forename: Xiang Qun
authors.initials: XQ
authors.lastname: Shi
authors.forename: Serge
authors.initials: S
authors.lastname: Rivest
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D018801:CD2 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005070:Evans Blue; D005260:Female; D019793:Fluorescein; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D018836:Inflammation Mediators / Q000008:administration & dosage; D016753:Interleukin-10 / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D007456:Iodine Isotopes / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055806:Microvessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009437:Neuralgia / Q000209:etiology; D062793:Occludin; D010539:Permeability; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors; D062826:Zonula Occludens-1 Protein
chemical_list: D001798:Blood Proteins; D018801:CD2 Antigens; D017252:CD3 Complex; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D007456:Iodine Isotopes; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; C568987:Ocln protein, rat; D010750:Phosphoproteins; D018125:Receptors, Transforming Growth Factor beta; C569043:Tjp1 protein, mouse; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D016753:Interleukin-10; D049452:Green Fluorescent Proteins; D005070:Evans Blue; D019793:Fluorescein