MMP (Matrix Metalloprotease)-9-Producing Monocytes Enable T Cells to Invade the Vessel Wall and Cause Vasculitis

Circ Res. 2018 Aug 31;123(6):700-715. doi: 10.1161/CIRCRESAHA.118.313206.


Rationale: Giant cell arteritis (GCA)-a primary vasculitis of medium and large arteries-is associated with vessel wall damage, elastic membrane fragmentation, and vascular remodeling. Proteinases are believed to contribute to pathogenesis by degrading extracellular matrix and causing tissue injury.

Objective: The MMP (matrix metalloproteinase)-9-a type IV collagenase-is produced in the vasculitic lesions of GCA. It is unknown which pathogenic processes are MMP-9 dependent.

Methods and results: The tissue transcriptome of GCA-affected temporal arteries contained high amounts of MMP-9 transcripts, and immunostaining for pro-MMP-9 localized the enzyme to wall-infiltrating macrophages. MMP-2 and MMP-9 transcripts were also abundant in monocytes and monocyte-derived macrophages from patients with GCA. Patient-derived monocytes outperformed healthy monocytes in passing through engineered basement membranes. GCA CD (cluster of differentiation) 4+ T cells required MMP-9-producing monocytes to penetrate through matrix built from type IV collagen. In vivo functions of MMP-9 were tested in a human artery-SCID (severe combined immunodeficiency) chimera model by blocking enzyme activity with a highly specific monoclonal antibody or by injecting rMMP-9 (recombinant MMP-9). Inhibiting MMP-9 activity profoundly suppressed vascular injury, decreased the density of inflammatory infiltrates ( P<0.001), reduced intramural neoangiogenesis ( P<0.001), and prevented intimal layer hyperplasia ( P<0.001). rMMP-9 amplified all domains of vasculitic activity, promoted assembly of T-cell infiltrates ( P<0.05), intensified formation of new microvessels ( P<0.001), and worsened intimal thickening ( P<0.001). Systemic delivery of N-acetyl-proline-glycine-proline-a matrikine produced by MMP-9-mediated gelatinolysis-had limited vasculitogenic effects.

Conclusions: In large vessel vasculitis, MMP-9 controls the access of monocytes and T cells to the vascular wall. T cells depend on MMP-9-producing monocytes to pass through collagen IV-containing basement membrane. Invasion of vasculitogenic T cells and monocytes, formation of neoangiogenic networks, and neointimal growth all require the enzymatic activity of MMP-9, identifying this protease as a potential therapeutic target to restore the immunoprivilege of the arterial wall in large vessel vasculitis.

Keywords: T lymphocytes; basement membrane; giant cell arteritis; macrophages; matrix metalloproteinases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Antibodies, Monoclonal / pharmacology
  • Axillary Artery / drug effects
  • Axillary Artery / enzymology*
  • Axillary Artery / immunology
  • Axillary Artery / pathology
  • Basement Membrane / enzymology
  • Basement Membrane / pathology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / enzymology*
  • CD4-Positive T-Lymphocytes / immunology
  • Case-Control Studies
  • Cell Movement* / drug effects
  • Cells, Cultured
  • Female
  • Giant Cell Arteritis / enzymology*
  • Giant Cell Arteritis / immunology
  • Giant Cell Arteritis / pathology
  • Giant Cell Arteritis / prevention & control
  • Humans
  • Male
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Matrix Metalloproteinase Inhibitors / pharmacology
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Monocytes / drug effects
  • Monocytes / enzymology*
  • Monocytes / immunology
  • Neointima
  • Neovascularization, Pathologic
  • Signal Transduction
  • Temporal Arteries / drug effects
  • Temporal Arteries / enzymology*
  • Temporal Arteries / immunology
  • Temporal Arteries / pathology
  • Vascular Remodeling* / drug effects


  • Anti-Inflammatory Agents
  • Antibodies, Monoclonal
  • Matrix Metalloproteinase Inhibitors
  • MMP9 protein, human
  • Matrix Metalloproteinase 9