TNFalpha-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve.
Matrix metalloproteinase-9 (MMP-9) is an extracellular protease that is induced hours after injury to peripheral nerve. This study shows that MMP-9 gene deletion and neutralization with MMP-9 antibody reduce macrophage content in injured wild-type nerves. In mice with delayed Wallerian degeneration (WldS), MMP-9 and tumor necrosis factor alpha (TNFalpha) decline in association with the reduced macrophage recruitment to injured nerve that characterizes this strain of mice. We further determined that TNFalpha acts as an MMP-9 inducer by establishing increased MMP-9 levels after TNFalpha injection in rat sciatic nerve in vivo and primary Schwann cells in vitro. We found reduced MMP-9 expression in crushed TNFalpha knockout nerves that was rescued with exogenous TNFalpha. Finally, local application of MMP-9 on TNFalpha-/- nerves increased macrophage recruitment to the lesion. These data suggest that TNFalpha lies upstream of MMP-9 in the pathway of macrophage recruitment to injured peripheral nerve.
Shubayev
Veronica I
VI
San Diego VA Healthcare System, CA 92161, USA. vshubayev@ucsd.edu
Angert
Mila
M
Dolkas
Jennifer
J
Campana
W Marie
WM
Palenscar
Kai
K
Myers
Robert R
RR
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010525:Peripheral Nerves / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D014855:Wallerian Degeneration / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9