Matrix metalloproteinases: Expression, regulation and role in the immunopathology of tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb) leads to approximately 1.5 million human deaths every year. In pulmonary tuberculosis (TB), Mtb must drive host tissue destruction to cause pulmonary cavitation and dissemination in the tissues. Matrix metalloproteinases (MMPs) are endopeptidases capable of degrading all components of pulmonary extracellular matrix (ECM). It is well established that Mtb infection leads to upregulation of MMPs and also causes disturbance in the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), thus altering the extracellular matrix deposition. In TB, secretion of MMPs is mainly regulated by NF-κB, p38 and MAPK signalling pathways. In addition, recent studies have demonstrated the immunomodulatory roles of MMPs in Mtb pathogenesis. Researchers have proposed a new regimen of improved TB treatment by inhibition of MMP activity to hinder matrix destruction and to minimize the TB-associated morbidity and mortality. The proposed regimen involves adjunctive use of MMP inhibitors such as doxycycline, marimastat and other related drugs along with front-line anti-TB drugs to reduce granuloma formation and bacterial load. These findings implicate the possible addition of economical and well-tolerated MMP inhibitors to current multidrug regimens as an attractive mean to increase the drug potency. Here, we will summarize the recent advancements regarding expression of MMPs in TB, their immunomodulatory role, as well as their potential as therapeutic targets to control the deadly disease.

Keywords: Mtb; Host-directed therapy; Immunopathology; MMPs; Signalling pathways.

Figure 1

Role of bradykinin signalling in expression and regulation of MMPs in non‐TB conditions. Bradykinin stimulation can lead to activation of intracellular signalling pathways which in turn induces various MMP secretion. Both B1R and B2R can activate ERK1/2 kinases eventually leading to increased expression of MMP‐1 and MMP‐9 in breast cancer and tracheal smooth muscles, respectively. Similarly, exogenous bradykinin treatment of granulosa cells induced MMP‐3 and MMP‐20 explaining their role in ovulation

Figure 2

Expression and regulation of MMPs in TB. In Mtb infection, there is upregulation of many MMPs which are contributing to TB pathology. The expression and secretion of MMPs are strictly regulated as excess of these enzymes may cause tissue destruction. Many studies have investigated these signalling pathways. P38/COXII/PGE2/cAMP is well‐established signalling cascade involved in the regulation of MMP‐1. In a recent study, IL‐17‐mediated regulation of MMP‐3 was dependent on MAPK. In addition, TNF‐α and HDAC1 can also regulate MMP‐1 and MMP‐9, and MMP‐1 and MMP‐3, respectively. As the excess of these MMPs may be detrimental for host and may exaggerate the TB pathology, therefore, inhibition of these signalling pathways may provide a new avenue for host‐directed therapy in TB

Figure 3

Role of MMPs in pulmonary granuloma and cavitation. Many studies have reported the increased expression of various MMPs in TB. Each of these MMPs has immunomodulatory role in the pathogenesis of TB. But MMP‐1, MMP‐3 and MMP‐9 are the most widely studied MMPs in TB, and their role in TB development has been well demonstrated. MMP‐9 upregulation is related to the recruitment of monocytes and macrophages at the site of infection, and these cells are main players of host innate immune response and are also crucial for granuloma formation. Upregulation of MMP‐9 in Mtb infection and as a result lung tissue remodelling is considered as mycobacterial strategy to create a suitable environment in host lung tissues. In contrast to MMP‐9, MMP‐1 degrades ECM as its primary function. ECM destruction leads to necrosis and cavitation thereby providing an immune‐privileged site for bacterial proliferation. MMPs such as MMP‐3, MMP‐8, MMP‐13 and others are also involved in tissue remodelling in TB. Detailed knowledge of these MMPs’ expression and function may help to devise a strategy to control the replication and spread of Mtb in host tissues