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Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in

Amit Bar-Or1, Robert K Nuttall, Martin Duddy

  • 1Montreal Neurological Institute, Quebec, Canada.

Brain : a Journal of Neurology
|September 25, 2003
PubMed

Insights

Matrix metalloproteinases (MMPs) are key in multiple sclerosis neuroinflammation. Monocytes express many MMPs, aiding blood-brain barrier crossing and identifying MMP-2 and MMP-14 as potential therapeutic targets.

Area of Science:

  • Neuroimmunology
  • Molecular Biology
  • Biochemistry

Background:

  • Matrix metalloproteinases (MMPs) are implicated in multiple sclerosis (MS) pathogenesis, potentially facilitating leukocyte infiltration into the central nervous system (CNS).
  • Previous research has focused on a limited number of MMPs, leaving the roles of most of the 23 MMP family members in MS unclear.

Purpose of the Study:

  • To systematically analyze the expression of all 23 MMP members in distinct leukocyte subsets from healthy individuals.
  • To investigate the differential expression of MMPs in B cells, T lymphocytes, and monocytes.
  • To identify specific MMPs that may be critical in the multiple sclerosis disease process.

Main Methods:

  • Quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the expression of all 23 MMP family members.
  • Leukocytes were isolated from the blood of normal individuals into distinct cellular populations (B cells, T lymphocytes, monocytes).
  • Monocyte migration across a model of the blood-brain barrier was assessed in vitro.

Main Results:

  • Distinct MMP expression patterns were observed across leukocyte subsets: MMP-11, MMP-26, MMP-27 in B cells; MMP-15, MMP-16, MMP-24, MMP-28 in T lymphocytes.
  • Monocytes showed enrichment of a majority of MMP members, including MMP-1, MMP-3, MMP-9, MMP-10, MMP-14, MMP-19, MMP-25, MMP-2, and MMP-17.
  • Monocytes exhibited more rapid migration across a blood-brain barrier model compared to T or B lymphocytes, correlating with their high MMP expression.
  • Elevated levels of MMP-2 and MMP-14 were found in monocytes from multiple sclerosis patients compared to normal individuals.
  • Tissue inhibitor of metalloproteinases (TIMP)-2 was also elevated in monocytes from multiple sclerosis patients.

Conclusions:

  • Monocytes are significant contributors to neuroinflammation in multiple sclerosis due to their extensive MMP expression.
  • The findings highlight specific MMPs, particularly MMP-2 and MMP-14, as potential therapeutic targets for multiple sclerosis.
  • The elevated MMP-2 and TIMP-2 in monocytes suggests a mechanism involving MMP-14 and TIMP-2 in MMP-2 activation, contributing to disease pathology.

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