The paradox of matrix metalloproteinases in infectious disease

Abstract

SummaryMatrix metalloproteinases (MMPs) are a family of proteolytic enzymes that perform multiple roles in the normal immune response to infection. MMPs facilitate leucocyte recruitment, cytokine and chemokine processing, defensin activation and matrix remodelling. However, excess MMP activity following infection may lead to immunopathology that causes host morbidity or mortality and favours pathogen dissemination or persistence. Here, we review the normal functions of MMPs in immunity and then discuss viral and bacterial infections where excess MMP activity has been implicated in pathology, specifically examining HIV, HTLV-1, hepatitis B, endotoxin shock, Helicobacter pylori and Mycobacterium tuberculosis . Tissue destruction may be exacerbated further by bacterial-derived enzymes which activate the host proMMPs. Finally, the potential for therapeutic targeting of excess MMP activity in infection is considered.

Multiple expression of matrix metalloproteinases in murine neurocysticercosis: Implications for leukocyte migration through multiple central nervous system barriers

“…MMP function has been classically associated with remodeling of the ECM, but their role in leukocyte recruitment and processing of cytokines, chemokines, defensins and adhesion molecules is increasingly apparent [19,63]. These multifunctional capabilities suggest that several members of this family are involved in the inflammatory process, and our results showing upregulation of multiple MMPs at the RNA level support this hypothesis albeit distinguishing between pro-and active MMPs is essential.…”

“…In addition, direct contact between leukocytes accumulated in these infiltrates can induce additional expression of MMPs [17]. Moreover, MMPs also modulate the expression and secretion of cytokines and chemokines that promote or restrict further leukocyte extravasation and immune cell interaction in inflammatory infiltrates [19,30,34]. As the immune infiltrates found during the course of murine NCC are composed of a heterogeneous population of immune cells including macrophages, γδ T cells, αβ T cells, neutrophils, and B cells [2,12], mechanisms that upregulate or downregulate the overall immune response via cleavage of cytokine, chemokine and adhesion molecules could be accomplished by the multiple expression of MMPs.…”

“…Upon infection the challenged host immune system must recruit leukocytes to the site of infection, eliminate the pathogen and then downregulate the response to allow resolution of the inflammatory process. MMPs play an important role in these processes both by degrading components of the ECM and by modulating cytokine and chemokine activity [19].…”

Matrix metalloproteinase polymorphisms and HIV anti-retroviral drugs: new implications of pharmacogenomics in therapeutic approaches

“…1,6 In particular, MMPs have key roles in normal immune response to infection through degradation of extracellular matrix, allowing leukocyte migration and modulating the activity of cytokines, chemokines and defensins. 7 The loss of regulation on MMP activity after infection may lead to tissue damage, microbial dissemination and associated immune pathologies. 7 In this respect, MMPs are involved and also have important roles in human immunodeficiency virus (HIV) infection, 8,9 in which an altered production and secretion of MMPs and TIMPs contributes to dysregulation in T cells, monocyte/macrophage and dendritic cell trafficking, as well as viral dissemination through extracellular matrix degradation.…”

“…7 The loss of regulation on MMP activity after infection may lead to tissue damage, microbial dissemination and associated immune pathologies. 7 In this respect, MMPs are involved and also have important roles in human immunodeficiency virus (HIV) infection, 8,9 in which an altered production and secretion of MMPs and TIMPs contributes to dysregulation in T cells, monocyte/macrophage and dendritic cell trafficking, as well as viral dissemination through extracellular matrix degradation. 8 To reduce the detrimental effects of MMP overexpression, several approaches have been widely used in clinical therapeutic practice, 9 including tetracyclines, 10 statins 11 and anti-retroviral drugs (in particular HIV protease inhibitors), 12 which are gold standards for HIV infection treatment.…”