Monocyte‐dependent oncostatin M and TNF‐α synergize to stimulate unopposed matrix metalloproteinase‐1/3 secretion from human lung fibroblasts in tuberculosis

Abstract

Leukocyte-derived matrix metalloproteinases (MMP) are implicated in the tissue destruction characteristic of tuberculosis (TB). The contribution of lung stromal cells to MMP activity in TB is unknown. Oncostatin M (OSM) is an important stimulus to extrapulmonary stromal MMP induction, but its role in regulation of pulmonary MMP secretion or pathophysiology of TB is unknown. We investigated OSM secretion from Mycobacterium tuberculosis (Mtb)-infected human monocytes/macrophages and the networking effects of such OSM on lung fibroblast MMP secretion. Mtb increased monocyte OSM secretion dose dependently in vitro. In vivo tuberculous granulomas immunostained positively for OSM. Further, conditioned media from Mtb-infected monocytes (CoMTb) induced monocyte OSM secretion (670 AE 55 versus 166 AE 14 pg/mL in controls), implicating an autocrine loop. Mtbinduced OSM secretion was prostaglandin (PG) sensitive, and required activation of surface G-protein coupled receptors. OSM induction was ERK MAP kinase dependent, p38-requiring but JNK-independent. OSM synergized with TNF-a, a key cytokine in TB granuloma formation, to stimulate pulmonary fibroblast MMP-1/-3 secretion, while suppressing secretion of tissue inhibitors of metalloproteinases-1/-2. In summary, Mtb infection of monocytes results in PG-dependent OSM secretion, which synergizes with TNF-a to drive functionally unopposed fibroblast MMP-1/-3 secretion, demonstrating a previously unrecognized role for OSM in TB.Key words: Human Á Inflammation Á Monocytes/macrophages Á Stromal cells Introduction Tuberculosis (TB) remains a major global health problem with over 8 million cases of overt clinical infection, and 2 million deaths annually. The pathological response to Mycobacterium tuberculosis (Mtb) infection is characterised by extensive tissue breakdown including caseous necrosis, and later fibrosis. Tissue destruction in TB requires degradation of matrix proteins including collagen and elastin, and several studies have implicated matrix metalloproteinases (MMP) in pathogenesis [1][2][3]. MMP are a group of 23 related zinc-dependent enzymes that together are capable of degrading all components of the extracellular matrix (ECM) [4]. MMP are inhibited in vivo by the tissue inhibitors of metalloproteinases (TIMP), and in general, overall proteolytic activity is determined by the molar ratio of MMP:TIMP. MMP secretion is induced by inflammatory cytokines, physical stimuli, or directly by some bacterial components [5]. Direct infection of mononuclear cells with Mtb has been shown to induce MMP-9 (gelatinase B), a process that depends in part on 6].In the lung, the principal structural supporting collagen is type I [7,8]. MMP-1 (interstitial collagenase) is the most abundant pulmonary enzyme capable of degrading type I collagen [5]. Several cell types secrete MMP-1 in TB [9,10] but there are no data on the role of fibroblast-derived MMP-1 in TB. However, stimulated fibroblasts are the most potent source of MMP-1 in the lung [11] and may cause type IV collagen and prote...

Matrix metalloproteinases in tuberculosis

“…Since stromal cells are more numerous in the lung and may express relatively greater levels of MMPs than monocytic cells [61], they represent a potentially important source of MMPs in TB. Monocyteepithelilal cell networks upregulate MMP-1 and -9 [35,36], while monocyte-fibroblast networks upregulate MMP-1 and -3 [62,63]. In our cellular model of TB meningitis, monocyteastrocyte networks were found to upregulate MMP-1, -2, -3, -7 and -9 gene expression [41].…”

Mycobacterium tuberculosis Upregulates Microglial Matrix Metalloproteinase-1 and -3 Expression and Secretion via NF-κB– and Activator Protein-1–Dependent Monocyte Networks

“…In work delineating the role of MMPs in pulmonary TB, we have demonstrated that MMP-9 is upregulated in M. tuberculosis infection by several cell types. However, upregulation of MMP-1 (collagenase-1) and MMP-3 (stromelysin-1, whose functions include MMP-1 activation) appeared relatively TB-specific (17)(18)(19). In CNS TB, we demonstrated that astrocytes secrete only MMP-9 (gelatinase B) in response to monocyte-dependent networks, despite upregulation of other MMP transcripts (20).…”

MMP-1 drives immunopathology in human tuberculosis and transgenic mice

“…The relative role of MMP-1 will be underestimated in this model, since stromal cell MMP secretion driven by M. tuberculosis will be absent (27,31,32). The lack of a functional ortholog of MMP-1 in mice would explain why infection of immunodeficient mice can result in extremely high bacterial loads and necrosis but cavitation does not occur (4,5).…”