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TNFalpha-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve

Veronica I Shubayev1, Mila Angert, Jennifer Dolkas

  • 1San Diego VA Healthcare System, CA 92161, USA. vshubayev@ucsd.edu

Molecular and Cellular Neurosciences
|November 22, 2005
PubMed

Insights

Tumor necrosis factor alpha (TNFalpha) induces matrix metalloproteinase-9 (MMP-9) production, which is crucial for recruiting macrophages to injured peripheral nerves. Targeting this pathway may enhance nerve repair.

Area of Science:

  • Neuroscience
  • Immunology
  • Molecular Biology

Background:

  • Matrix metalloproteinase-9 (MMP-9) is an extracellular protease upregulated after peripheral nerve injury.
  • Macrophage recruitment is essential for clearing debris and promoting regeneration following nerve damage.
  • The upstream regulators of MMP-9 in peripheral nerve injury remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of MMP-9 in macrophage recruitment to injured peripheral nerves.
  • To investigate the relationship between tumor necrosis factor alpha (TNFalpha) and MMP-9 expression in nerve injury.
  • To determine if TNFalpha acts as an inducer of MMP-9 in the context of peripheral nerve damage.

Main Methods:

  • Utilized MMP-9 gene deletion and antibody neutralization in mouse models of peripheral nerve injury.
  • Examined macrophage content in injured nerves from wild-type, WldS, and TNFalpha knockout mice.
  • Administered TNFalpha in vivo (rat sciatic nerve) and in vitro (primary Schwann cells) to assess MMP-9 induction.
  • Investigated the effect of exogenous MMP-9 application on macrophage recruitment in TNFalpha-deficient nerves.

Main Results:

  • MMP-9 gene deletion and antibody neutralization significantly reduced macrophage infiltration in injured nerves.
  • Mice with delayed Wallerian degeneration (WldS) exhibited lower MMP-9 and TNFalpha levels, correlating with reduced macrophage recruitment.
  • TNFalpha administration increased MMP-9 levels in both in vivo and in vitro models, indicating TNFalpha as an MMP-9 inducer.
  • Exogenous MMP-9 application enhanced macrophage recruitment to the lesion site in TNFalpha knockout nerves.

Conclusions:

  • TNFalpha plays a critical upstream role in inducing MMP-9 expression following peripheral nerve injury.
  • The TNFalpha-MMP-9 axis is a key pathway regulating macrophage recruitment to sites of nerve damage.
  • This pathway represents a potential therapeutic target for modulating inflammatory responses and promoting peripheral nerve repair.

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