Upregulation and interaction of TNF alpha and gelatinases A and B in painful peripheral nerve injury

Chronic constriction injury (CCI) to peripheral nerve causes a painful neur opathy in association with a process of axonal degeneration and endoneural remodeling that involves macrophage recruitment and local increase in extra cellular proteases and tumor necrosis factor alpha (TNF-alpha). Cell surfac e activation of TNF-alpha from its transmembrane precursor, as well as sequ estration of TNF-alpha receptors II and I, is performed by the zinc-depende nt endopeptidase family of matrix metalloproteinases (MMPs). Among TNF-alph a-converting MMPs, basal lamina degrading gelatinases are thought to play a role in sciatic nerve injury. In the present study, we determined the form s of TNF-alpha involved in the development of CCI neuropathy in rats, using Western blot analysis, and the temporal correlation of TNF-alpha and TNFRI protein profiles with gelatinases activity at the site of peripheral nerve injury. We observed two peaks in TNF-alpha protein during the first week o f 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-alpha protein released by residen t Schwann cells, mast cells and macrophages. This peak in TNF-alpha protein expression corresponds to an increase in gelatinase B (MMP-9) activity, wh ich is greatly upregulated as early as 3 h following CCI to rat sciatic ner ve. The second peak occurs at 5 days post-CCI, and may represent TNF-alpha protein released by hematogenously recruited macrophages. This peak is mark ed by the increase in active soluble 17 kDa TNF-alpha and by gelatinase A ( MMP-2) upregulation. These observations suggest that there is a pathogenic role for the TNF-alpha-converting function of MMP-2 in painful CCI neuropat hy. We conclude that severe nerve injury induces MMPs, TNF-alpha and TNFRI, which interactively control the privileged endoneurial environment and the pathogenesis of the painful neuropathies associated with the macrophage-de pendent processes of Wallerian degeneration. (C) 2000 Elsevier Science B.V. All rights reserved.