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.
Highlights
Tuberculosis (TB) is a major threat to public health worldwide, and it continues to kill more than 1.5 million people annually.[1]
Mycobacterium tuberculosis (Mtb) can be recognized through pattern recognition receptors (PRRs) such as Toll‐like recep‐ tors (TLRs) and Nod‐like receptors (NLRs).[5]
This regulation is mainly carried out by tissue inhibitors of metalloproteinases (TIMPs) as unstimulated human peripheral blood monocytes, B cells and T cells express higher levels of TIMP‐1, TIMP‐2 and TIMP‐4.37 Pulmonary epithelial cells are a significant source of Matrix metalloprotein‐ ases (MMPs) as they express many MMPs including MMP‐1, MMP‐2, MMP‐7 and MMP‐9.38 In many pathological conditions, cell migration is closely linked to degradation of the extracellular matrix (ECM) and the activated MMPs are con‐ sidered as a prerequisite for invasion and metastasis of cancerous cells.[39]
Summary
Tuberculosis (TB) is a major threat to public health worldwide, and it continues to kill more than 1.5 million people annually.[1]. MMPs consist of 23 members in human and are expressed in almost all organs and tissues.[16] These enzymes have key roles in inflammatory cell mi‐ gration, tissue repair, chemokine and cytokine signalling, degradation of matrix and non‐matrix proteins, pathogenesis of various diseases and modulation of immune responses.[17-21]. Many immune cells express low levels of MMPs in the resting state, and expression of MMPs is upregulated by exogenous stimuli, cytokines and cell‐cell interaction.[36] This regulation is mainly carried out by TIMPs as unstimulated human peripheral blood monocytes, B cells and T cells express higher levels of TIMP‐1, TIMP‐2 and TIMP‐4.37 Pulmonary epithelial cells are a significant source of MMPs as they express many MMPs including MMP‐1, MMP‐2, MMP‐7 and MMP‐9.38 In many pathological conditions, cell migration is closely linked to degradation of the ECM and the activated MMPs are con‐ sidered as a prerequisite for invasion and metastasis of cancerous cells.[39].
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