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Classical macrophage activation up-regulates several matrix metalloproteinases through mitogen activated protein

Wei-Chun Huang1, Graciela B Sala-Newby, Angela Susana

  • 1Bristol Heart Institute, University of Bristol, Bristol, United Kingdom.

Plos One
|August 11, 2012
PubMed

Insights

Classical macrophage activation up-regulates matrix metalloproteinases (MMPs) and down-regulates TIMP-3, while alternative activation affects distinct MMPs and TIMP-3. This study identifies key signaling pathways for modulating MMP activity.

Area of Science:

  • Immunology and Molecular Biology
  • Extracellular Matrix Biology

Background:

  • Monocytes and macrophages remodel the extracellular matrix (ECM) via matrix metalloproteinases (MMPs).
  • Distinct roles of classically and alternatively activated macrophages are recognized, but their regulation of MMPs and inhibitors is not fully understood.

Purpose of the Study:

  • To comprehensively investigate the regulation of MMPs and their inhibitors (TIMPs) by classical and alternative macrophage activation.
  • To identify the signaling pathways involved in MMP regulation during macrophage activation.

Main Methods:

  • In vitro differentiation of macrophages (CD16+/- and CD16-) and stimulation with LPS, IL-1, TNFα, and IFNγ.
  • Analysis of steady-state mRNA levels for MMPs and TIMP-3.
  • Investigation of signaling pathways including MAPKs, PI3K, IKK-2, and JAK-2.
  • In vivo assessment of MMP activity in human atherosclerotic plaques.

Main Results:

  • Classical activation up-regulated MMP-1, -3, -7, -10, -12, -14, -25 and decreased TIMP-3 mRNA.
  • Alternative activation decreased MMP-2, -8, -19 but increased MMP-11, -12, -25, and TIMP-3 mRNA.
  • Classical activation-induced MMPs were dependent on MAPKs, PI3K, and IKK-2; IFNγ effects involved JAK-2. MMP-1 and -10 activity correlated with classical activation markers in atherosclerotic plaques.

Conclusions:

  • Classical macrophage activation selectively up-regulates specific MMPs and down-regulates TIMP-3, both in vitro and in vivo.
  • Alternative activation induces a distinct set of MMPs and TIMP-3.
  • The identified signaling pathways offer potential targets for selective modulation of MMP activity.

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