Endoneurial remodeling by TNFalph- and TNFalpha-releasing proteases. A spatial and temporal co-localization study in painful neuropathy.

Peripheral nerve injury causing Wallerian degeneration results in endoneurial remodeling initiated by an increase in tumor necrosis factor-alpha (TNF), which is activated from its precursor by extracellular proteases of the matrix metalloproteinase (MMP) family. We used immunohistochemistry to analyze the distribution of TNF, TNF-releasing MMPs, including gelatinases (MMP-2 and MMP-9), and TNF-alpha converting enzyme (TACE) in painful neuropathy caused by chronic constriction injury of rat sciatic nerve. Tissue was analyzed at the injury site and in the corresponding L4 and L5 dorsal root ganglia (DRG) throughout the time-course of the neuropathy. Using confocal laser scanning microscopy, we co-localized TNF with each MMP, and observed spatial and temporal distinction in their distribution. TNF co-localized in vessel endothelium with MMP-2 and in macrophages with MMP-9 and TACE at the period of active immune cell migration. TNF co-localized with myelin degrading MMP-9 within Schwann cells during demyelination, and intraaxonally during remyelination. These studies were performed to explore the role of basal-lamina degrading gelatinases and other TNF-releasing MMPs in TNF-mediated Wallerian degeneration. The data provided in this study may be useful in designing selective therapy for painful neuropathy using synthetic hydroxamate MMP inhibitors.