Unopposed Matrix Metalloproteinase-9 Expression in Human Tuberculous Granuloma and the Role of TNF-α-Dependent Monocyte Networks

Abstract

Tuberculosis is characterized by granuloma formation and caseous necrosis, but the factors causing tissue destruction are poorly understood. Matrix metalloproteinase (MMP)-9 (92-kDa gelatinase) secretion from monocytes is stimulated by Mycobacterium tuberculosis (M. tb) and associated with local tissue injury in tuberculosis patients. We demonstrate strong immunohistochemical MMP-9 staining in monocytic cells at the center of granuloma and adjacent to caseous necrosis in M. tb-infected patient lymph nodes. Minimal tissue inhibitor of MMPs-1 staining indicated that MMP-9 activity is unopposed. Because granulomas characteristically contain few mycobacteria, we investigated whether monocyte-monocyte cytokine networks amplify MMP-9 secretion. Conditioned medium from M. tb-infected primary human monocytes or THP-1 cells (CoMTB) stimulated MMP-9 gene expression and a >10-fold increase in MMP-9 secretion by monocytes at 3–4 days (p < 0.009, vs controls). Although CoMTB stimulated dose-dependent MMP-9 secretion, MMP-1 (52-kDa collagenase) was not induced. Anti-TNF-α Ab but not IL-1R antagonist pretreatment decreased CoMTB-induced MMP-9 secretion by 50% (p = 0.0001). Anti-TNF-α Ab also inhibited MMP-9 secretion from monocytic cells by 50%, 24 h after direct M. tb infection (p = 0.0002). Conversely, TNF-α directly stimulated dose-dependent MMP-9 secretion. Pertussis toxin inhibited CoMTB-induced MMP-9 secretion and enhanced the inhibitory effect of anti-TNF-α Ab (p = 0.05). Although chemokines bind to G protein-linked receptors, CXCL8, CXCL10, CCL2, and CCL5 did not stimulate monocyte MMP-9 secretion. However, the response to cholera toxin confirmed that G protein signaling pathways were intact. In summary, MMP-9 within tuberculous granuloma is associated with tissue destruction, and TNF-α, critical for antimycobacterial granuloma formation, is a key autocrine and paracrine regulator of MMP-9 secretion.

Immunity and Immunopathology in the Tuberculous Granuloma

“…MMP9 levels are elevated in human TB (Price et al 2003;Sheen et al 2009), and in lung TB, it is expressed prominently in the epithelium surrounding the granulomas in addition to the macrophages themselves (Elkington et al 2007). Among pleural TB patients, pleural fluid MMP9 concentrations are higher in those patients with granulomatous pleural disease than in those with nongranulomatous disease (Sheen et al 2009).…”

“…Among pleural TB patients, pleural fluid MMP9 concentrations are higher in those patients with granulomatous pleural disease than in those with nongranulomatous disease (Sheen et al 2009). Among tuberculous meningitis patients, increased MMP9 levels in the cerebrospinal fluid are associated with worse outcomes (Price et al 2003). In a mouse model of M. tuberculosis aerosol infection, MMP9 knockout mice recruited fewer macrophages to the lung and formed smaller granulomas, features that were associated with reduced lung bacterial loads as early as 2 wk postinfection and continuing through the 120-d assay period (Taylor et al 2006).…”

Polymorphisms in the TNF-α Promoter and Variability in the Granulomatous Response in Patients with Crohn's Disease

“…Polymorphisms that have been reported to increase (308G/A) or decrease circulating TNF-␣ (238G/A, 857 C/T, 863 C/A) (27)(28)(29)(30)(31)(32)(33), as well as playing a possible role in disease phenotype and susceptibility (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39). The 857C/T and 863C/A polymorphisms appear to be located at transcription factor binding sites (32,34,35).…”

Expression of chemokines and gelatinase B in sympathetic ophthalmia

“…54 Similarly, previous studies demonstrated immunoreactivity for gelatinase B in epithelioid cells, multinucleated giant cells, and macrophages within granulomas in other human granulomatous disorders. [55][56][57] Expression of gelatinase B has been associated with a wide variety of pathological processes, including autoimmune diseases such as multiple sclerosis, 58 rheumatoid arthritis, 59 and type I diabetes. 60 The mechanism of action of gelatinase B in the pathogenesis of autoimmunity may be through the cleavage of substrate proteins into immunodominant epitopes.…”