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

Abstract

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.