The blood-nerve barrier (BNB) is a dynamic and competent interface between the endoneurial microenvironment and the surrounding extracellular space or blood. It is localised at the innermost layer of the multilayered ensheathing perineurium and endoneurial microvessels, and is the key structure that controls the internal milieu of the peripheral nerve parenchyma. Since the endoneurial BNB is the point of entry for pathogenic T cells and various soluble factors, including cytokines, chemokines and immunoglobulins, understanding this structure is important to prevent and treat human immune mediated neuropathies such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) syndrome and a subset of diabetic neuropathy. However, compared with the blood-brain barrier, only limited knowledge has been accumulated regarding the function, cell biology and clinical significance of the BNB. This review describes the basic structure and functions of the endoneurial BNB, provides an update of the biology of the cells comprising the BNB, and highlights the pathology and pathomechanisms of BNB breakdown in immune mediated neuropathies. The human immortalised cell lines of BNB origin established in our laboratory will facilitate the future development of BNB research. Potential therapeutic strategies for immune mediated neuropathies manipulating the BNB are also discussed.
"These findings might not reflect the direct effects of VEGF alone, because multiple inflammatory cytokines such as interleukin-12, and tumor necrosis-a are simultaneously and markedly upregulated in the active phase of POEMS syndrome (Kanai et al., 2012), and it is possible such cytokines other than VEGF affect ion channel function, although this should be investigated in further studies. Nevertheless, increased vascular permeability mediated by VEGF presumably responsible for nerve edema, frequently found on pathological examination (Kanda, 2013). We initially expected membrane depolarization due to edema-induced compression ischemia in POEMS syndrome, and nerve edema detected by ultrasound partly correlated with axonal excitability. "
", 1995 ) or hematogenous ( Yoshizawa et al . , 1991 ) spread , but the absence of lymphatic vessels within endoneurium and the existence of blood – nerve barrier ( Kanda , 2013 ) make these theories unlikely . More recent studies have suggested that more complex reciprocal signaling interactions between cancer cells and nerves may be involved ( Liebig et al . "
"The BNB is made up of specialized endothelial cells within the endoneurium, along with the perineurial barrier. Under healthy conditions, the BNB acts as a selectively permeable barrier that creates an immunologically and biochemically privileged space for axons and supporting cells to function within . The importance of the BNB is further highlighted when we note that the endoneurial fluid has a different electrolyte composition than that of surrounding tissues and blood . "
[Show abstract][Hide abstract] ABSTRACT: The blood-nerve barrier (BNB) is a selectively permeable barrier that creates an immunologically and biochemically privileged space for peripheral axons and supporting cells. The breakdown of the BNB allows access of blood-borne (hematogenous) cells and molecules to the endoneurium to engage in the local inflammatory cascade. This process was examined in a mouse model of trauma associated neuropathic pain. The impact of nerve injury triggered-opening of the BNB in the development of chronic pain behavior was investigated. Partial ligation of the sciatic nerve led to a long-lasting disruption of the BNB distal to the site of injury. Vascular endothelial growth factor (VEGF) was expressed by resident macrophages after nerve injury. Intraneural injection of VEGF decreased mechanical thresholds while opening the BNB. Serum from nerve injured or LPS treated animals elicited mechanical allodynia in naive animals, when allowed to bypass the BNB by intraneural injection. Intraneural injection of fibrinogen, a clotting protein in plasma which was found to deposit in the nerve following nerve injury, also produced a decrease in mechanical thresholds when introduced into naive nerves. These results demonstrate that blood-borne molecules may play a role in the generation of neuropathic pain, suggesting that pain may be driven from infection or injury, at a distance from the nervous system. Furthermore, the breakdown of the BNB in neuropathic conditions was exploited to permit the entry of analgesic molecules that typically cannot pass the BNB, such as ProToxin-II, a BNB impermeable Nav1.7 inhibitor. Therapeutics utilizing this mechanism could have selective access to injured nerves over healthy tissues.
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