MMP-1 drives immunopathology in human tuberculosis and transgenic mice

Abstract

IntroductionMycobacterium tuberculosis infects one-third of the world's population (1) and is transmitted by the aerosol route. Although the mechanisms whereby M. tuberculosis evades the host immune response are increasingly well understood (2), those by which M. tuberculosis engages the immune response to drive tissue destruction and hence transmission are relatively poorly characterized (3). The events underlying this immunopathology are not well defined, in part because the mouse, one of the most useful models in which to study M. tuberculosis immunology, does not develop lung pathology similar to that of humans (4, 5). In humans, M. tuberculosis subverts the host immune response to drive proteolytic destruction of the extracellular matrix scaffold. The current paradigm of tuberculosis (TB) pathology proposes that caseation leads directly to cavitation (2, 4, 6). However, this model overlooks that fact that destruction of lung extracellular matrix must be driven by proteases. Fibrillar collagens provide the lung's tensile strength and are highly resistant to enzymatic degradation (7,8). Only collagenolytic MMPs can cleave these helical collagens at neutral pH (9).MMPs are a family of zinc-dependent proteases that can collectively degrade all components of the extracellular matrix (8). MMP activity is tightly regulated at the level of transcription and activation by proteolytic cleavage. MMPs are specifically inhibited by tissue inhibitor of metalloproteinases (TIMPs) (9). Excessive MMP activity is implicated in diverse pulmonary pathologies characterized by extracellular matrix destruction (8). However, despite the potentially key role of MMPs in lung matrix destruction in human TB, the central mechanisms resulting in tissue damage have not been defined.

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…Elkington and coworkers provide evidence that M. tuberculosis drives the expression of MMP-1, which in turn promotes the collagen breakdown that leads to alveolar destruction in TB. These findings identify putative therapeutic targets for the prevention of TB (Elkington et al, 2011).…”

“…Tuberculosis. Elkington and coworkers have shown that MMP-1 is highly upregulated in tuberculosis (Elkington et al, 2011), leading to the degradation of the major lung ECM components, such as type I collagen and elastin. MMP-1 expression in epithelial cells in culture is driven by a monocyte-dependent network.…”

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

“…While we cannot exclude that chemokines present in cmMTB could be involved in the migration capacity of CD16 + C-D163 + MerTK + pSTAT3 + monocyte-macrophages, we showed that STAT3-dependent acquisition of the M2-like phenotype is essential for the enhanced motility and extracellular matrix remodeling activity in these cells. This process is accompanied by MMP1 and MMP9 activity that may contribute to lung tissue damage and TB pathogenesis, as suggested by the formation of protease-mediated tunnels in 3D matrices [47,60,61], by a study demonstrating that MMP1 is increased during Mtb infection and is responsible for lung immunopathology [62], and by other reports evidencing the role of MMP9 in the recruitment of macrophages, granuloma maturation and bacterial dissemination [44]. This is an exciting finding given that, in the zebrafish and mouse models, mycobacteria infection recruits highly motile macrophages as a tool for bacterial dissemination [44,48].…”

Immunity and Immunopathology in the Tuberculous Granuloma

“…M. tuberculosis infection in humans induces MMP1 expression in epithelial cells surrounding the granuloma and in leukocytes (Elkington et al 2005). Overexpression of human MMP1 in mice infected with M. tuberculosis induced granuloma breakdown (Elkington et al 2011a). Although the specific mycobacterial signals that induce MMP1 (Ganachari et al 2010) have not been identified, it has been noted that M. bovis BCG is a poor inducer compared with virulent M. tuberculosis (Elkington et al 2005), suggesting that MMP1 induction might share similarities with that of MMP9.…”