Matrix Metalloproteinase-1 Is Regulated in Tuberculosis by a p38 MAPK-Dependent,<i>p</i>-Aminosalicylic Acid-Sensitive Signaling Cascade

Rand, Lucinda; Green, Justin A.; Saraiva, Luísa; Friedland, Jon S.; Elkington, Paul

doi:10.4049/jimmunol.0801935

Cited by 50 publications

(57 citation statements)

References 43 publications

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“…P-amino-salicylic acid, used to treat TB for 60 years but with a poorly defined mechanism of action, inhibits MMP-1 secretion by M. tuberculosis-infected macrophages (37), suggesting that an established treatment for TB may act by limiting tissue destruction. We demonstrate that Ro32-3555, a compound that has been used in phase III clinical trials for arthritis (11), can suppress M. tuberculosis-driven MMP-1 activity.…”

Section: Discussionmentioning

confidence: 99%

MMP-1 drives immunopathology in human tuberculosis and transgenic mice

Elkington¹,

Shiomi²,

Breen³

et al. 2011

J. Clin. Invest.

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202

230

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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.

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Section: Discussionmentioning

confidence: 99%

MMP-1 drives immunopathology in human tuberculosis and transgenic mice

Elkington¹,

Shiomi²,

Breen³

et al. 2011

J. Clin. Invest.

Self Cite

202

230

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“…The biochemistry of the lung extracellular matrix predicts that matrix metalloproteinases (MMPs) will be the dominant proteases driving lung matrix destruction in TB (12). We have shown that MMP-1 is a key collagenase up-regulated in patients with TB (13,14), and MMP-1 expression is suppressed by p-amino salicylic acid, an antituberculous agent used for 70 years but with an incompletely understood mechanism of action (15). In the zebrafish model, MMP-9 regulates monocyte recruitment to the granuloma (16), indicating that MMPs both modulate the immune response to Mycobacterium tuberculosis (Mtb) and drive pathology (17).…”

mentioning

confidence: 91%

“…Monocyte-derived primary human macrophages were infected with Mtb H37Rv as described (15), and this strain was used in all cellular experiments. Primary human bronchial epithelial cells (Lonza, Slough, UK) were cultured and stimulated with conditioned media from Mtb-infected monocytes (CoMtb) and A549 cells transiently transfected as described (22).…”

Section: Cell Culture Experimentsmentioning

confidence: 99%

Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

Walker

Clark²,

Oni

et al. 2012

Am J Respir Crit Care Med

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122

136

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Rationale: Tuberculosis kills more than 1.5 million people per year, and standard treatment has remained unchanged for more than 30 years. Tuberculosis (TB) drives matrix metalloproteinase (MMP) activity to cause immunopathology. In advanced HIV infection, tissue destruction is reduced, but underlying mechanisms are poorly defined and no current antituberculous therapy reduces host tissue damage. Objectives: To investigate MMP activity in patients with TB with and without HIV coinfection and to determine the potential of doxycycline to inhibit MMPs and decrease pathology. Methods: Concentrations of MMPs and cytokines were analyzed by Luminex array in a prospectively recruited cohort of patients. Modulation of MMP secretion and Mycobacterium tuberculosis growth by doxycycline was studied in primary human cells and TB-infected guinea pigs. Measurements and Main Results: HIV coinfection decreased MMP concentrations in induced sputum of patients with TB. MMPs correlated with clinical markers of tissue damage, further implicating dysregulated protease activity in TB-driven pathology. In contrast, cytokine concentrations were no different. Doxycycline, a licensed MMP inhibitor, suppressed TB-dependent MMP-1 and -9 secretion from primary human macrophages and epithelial cells by inhibiting promoter activation. In the guinea pig model, doxycycline reduced lung TB colony forming units after 8 weeks in a dose-dependent manner compared with untreated animals, and in vitro doxycycline inhibited mycobacterial proliferation. Conclusions: HIV coinfection in patients with TB reduces concentrations of immunopathogenic MMPs. Doxycycline decreases MMP activity in a cellular model and suppresses mycobacterial growth in vitro and in guinea pigs. Adjunctive doxycycline therapy may reduce morbidity and mortality in TB.Keywords: lung; mycobacteria; immunopathology; protease inhibitors Tuberculosis (TB) continues to kill more than 1.5 million people a year (1). Standard treatment for TB has remained unchanged for more than 30 years (2), and multidrug-and extensively drugresistant strains are progressively emerging (3, 4). Mortality rates remain high among patients even after they have commenced TB treatment (5, 6). A characteristic hallmark of TB is tissue destruction, causing morbidity, mortality, and transmission of infection. However, the mediators of this immunopathology are incompletely understood (7,8), preventing the design of rational therapies to reduce immunemediated host damage and improve outcomes in TB.TB is primarily a disease of the lung (9, 10). In advanced HIV infection, with severely reduced CD4 cell counts, TB infection is common, but there is reduced tissue destruction and cavitation rarely occurs (11). The underlying cause of divergent pathology in HIV-TB coinfection is poorly defined, and greater understanding of this tissue destruction may identify novel therapeutic approaches to limit morbidity and mortality. The biochemistry of the lung extracellular matrix predicts that matrix metalloproteinases (MMPs) will be ...

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“…Both the p38 and extracellular signal-related kinase/mitogenactivated protein kinase (MAPK) pathways are critical in regulating MMP secretion in multiple cell types, both as a result of direct infection and intercellular networks [35,36,63,66,67]. Although p38 MAPK pathway activation has multiple effects, including mRNA stabilisation, in primary human macrophages one critical downstream effector is the cyclooxygenase (COX) pathway.…”

Section: Regulation Of Mmp Expressionmentioning

confidence: 99%

Matrix metalloproteinases in tuberculosis

Elkington¹,

Ugarte-Gil²,

Friedland³

2011

European Respiratory Journal

114

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Tuberculosis (TB) remains a global health pandemic. Infection is spread by the aerosol route and Mycobacterium tuberculosis must drive lung destruction to be transmitted to new hosts. Such inflammatory tissue damage is responsible for morbidity and mortality in patients. The underlying mechanisms of matrix destruction in TB remain poorly understood but consideration of the lung extracellular matrix predicts that matrix metalloproteinases (MMPs) will play a central role, owing to their unique ability to degrade fibrillar collagens and other matrix components. Since we proposed the concept of a matrix degrading phenotype in TB a decade ago, diverse data implicating MMPs as key mediators in TB pathology have accumulated. We review the lines of investigation that have indicated a critical role for MMPs in TB pathogenesis, consider regulatory pathways driving MMPs and propose that inhibition of MMP activity is a realistic goal as adjunctive therapy to limit immunopathology in TB.

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Matrix Metalloproteinase-1 Is Regulated in Tuberculosis by a p38 MAPK-Dependent,p-Aminosalicylic Acid-Sensitive Signaling Cascade

Cited by 50 publications

References 43 publications

MMP-1 drives immunopathology in human tuberculosis and transgenic mice

MMP-1 drives immunopathology in human tuberculosis and transgenic mice

Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

Matrix metalloproteinases in tuberculosis

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