Basement membrane and repair of injury to peripheral nerve: defining a potential role for macrophages, matrix metalloproteinases, and tissue inhibitor of metalloproteinases-1.
Injury to a peripheral nerve is followed by a remodeling process consisting of axonal degeneration and regeneration. It is not known how Schwann cell-derived basement membrane is preserved after injury or what role matrix metalloproteinases (MMPs) and their inhibitors play in axonal degeneration and regeneration. We showed that the MMPs gelatinase B (MMP-9), stromelysin-1 (MMP-3), and the tissue inhibitor of MMPs (TIMP)-1 were induced in crush and distal segments of mouse sciatic nerve after injury. TIMP-1 inhibitor activity was present in excess of proteinase activity in extracts of injured nerve. TIMP-1 protected basement membrane type IV collagen from degradation by exogenous gelatinase B in cryostat sections of nerve in vitro. In vivo, during the early phase (1 d after crush) and later phase (4 d after crush) after injury, induction of TNF-alpha and TGF-beta 1 mRNAs, known modulators of TIMP-1 expression, were paralleled by an upregulation of TIMP-1 and gelatinase B mRNAs. At 4 days after injury, TIMP-1, gelatinase B, and TNF-alpha mRNAs were localized to infiltrating macrophages and Schwann cells in the regions of nerve infiltrated by elicited macrophages. TIMP-1 and cytokine mRNA expression was upregulated in undamaged nerve explants incubated with medium conditioned by macrophages or containing the cytokines TGF-beta 1, TNF-alpha, and IL-1 alpha. These results show that TIMP-1 may protect basement membrane from uncontrolled degradation after injury and that cytokines produced by macrophages may participate in the regulation of TIMP-1 levels during nerve repair.
La Fleur
M
M
Department of Anatomy, University of California, San Francisco 94143-0750, USA.
Underwood
J L
JL
Rappolee
D A
DA
Werb
Z
Z
D000818:Animals; D001485:Basement Membrane / Q000502:physiology*; D017364:Collagenases / Q000096:biosynthesis*; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006023:Glycoproteins / Q000096:biosynthesis*; D007375:Interleukin-1 / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology*; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9; D051379:Mice; D008815:Mice, Inbred Strains; D009416:Nerve Regeneration; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D012038:Regeneration; D012583:Schwann Cells / Q000502:physiology; D012584:Sciatic Nerve / Q000293:injuries / Q000502:physiology*; D019714:Tissue Inhibitor of Metalloproteinases; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014945:Wound Healing
D017077:Culture Media, Conditioned; D016207:Cytokines; D006023:Glycoproteins; D007375:Interleukin-1; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D017364:Collagenases; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9