Upregulation And Interaction Of TNFα and Gelatinases A and B In Painful Peripheral Nerve Injury

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Chronic constriction injury (CCI) to peripheral nerve causes a painful neuropathy in association with a process of axonal degeneration and endoneurial remodeling that involves macrophage recruitment and local increase in extracellular proteases and tumor necrosis factor alpha (TNF‐α). Cell surface activation of TNF‐α from its transmembrane precursor, as well as sequestration of TNF‐α receptors II and I, is performed by the zinc‐dependent endopeptidase family of matrix metalloproteinases (MMPs). Among TNF‐α‐converting MMPs, basal lamina degrading gelatinases are thought to play a role in sciatic nerve injury. In the present study, we determined the forms of TNF‐α involved in the development of CCI neuropathy in rats, using Western blot analysis, and the temporal correlation of TNF‐α and TNFRI protein profiles with gelatinase activity at the site of peripheral nerve injury. We observed two peaks in TNF‐α protein during the first week of CCI that correspond to previously reported peaks in painful behavior. We propose that the first peak at 6 h post‐CCI is due to the local expression of the cytotoxic transmembrane 26 kDa TNF‐α protein released by resident Schwann cells, mast cells and macrophages. This peak in TNF‐α protein expression corresponds to an increase in gelatinase B (MMP‐9) activity, which is greatly upregulated as early as 3 h following CCI to rat sciatic nerve. The second peak occurs at 5 days post‐CCI, and may represent TNF‐α protein released by hematogenously recruited macrophages. This peak is marked by the increase in active soluble 17 kDa TNF‐α and by gelatinase A (MMP‐2) upregulation. These observations suggest that there is a pathogenic role for the TNF‐α‐converting function of MMP‐2 in painful CCI neuropathy. We conclude that severe nerve injury induces MMPs, TNF‐α and TNFRI, which interactively control the privileged endoneurial environment and the pathogenesis of the painful neuropathies associated with the macrophage‐dependent processes of Wallerian degeneration.