Cytokine regulation of MMP-9 in peripheral glia: implications for pathological processes and pain in injured nerve.
Matrix metalloproteinase-9 (MMP-9) is an extracellular protease that is induced in Schwann cells hours after peripheral nerve injury and controls axonal degeneration and macrophage recruitment to the lesion. Here, we report a robust (90-fold) increase in MMP-9 mRNA within 24 h after rat sciatic nerve crush (1 to 60 days time-course). Using direct injection into a normal sciatic nerve, we identify the proinflammatory cytokines TNF-alpha and IL-1beta as potent regulators of MMP-9 expression (Taqman qPCR, zymography). Myelinating Schwann cells produced MMP-9 in response to cytokine injection and crush nerve injury. MMP-9 gene deletion reduced unstimulated neuropathic nociceptive behavior after one week post-crush and preserved myelin thickness by protecting myelin basic protein (MBP) from degradation, tested by Western blot and immunofluorescence. These data suggest that MMP-9 expression in peripheral nerve is controlled by key proinflammatory cytokine pathways, and that its removal protects nerve fibers from demyelination and reduces neuropathic pain after injury.
Chattopadhyay
Sharmila
S
San Diego VA Healthcare System, USA.
Myers
Robert R
RR
Janes
Julie
J
Shubayev
Veronica
V
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000276:immunology / Q000378:metabolism; D017353:Gene Deletion; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D004676:Myelin Basic Protein / Q000276:immunology / Q000378:metabolism; D009409:Nerve Crush; D009413:Nerve Fibers, Myelinated / Q000276:immunology / Q000378:metabolism; D017288:Pain Threshold / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000378:metabolism*; D020426:Sciatic Neuropathy / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
D053583:Interleukin-1beta; D004676:Myelin Basic Protein; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9