<i>Mycobacterium tuberculosis</i> Upregulates Microglial Matrix Metalloproteinase-1 and -3 Expression and Secretion via NF-κB– and Activator Protein-1–Dependent Monocyte Networks

Green, Justin A.; Elkington, Paul; Pennington, Caroline J.; Roncaroli, Federico; Dholakia, Shruti; Moores, Rachel; Bullen, Anwen; Porter, Joanna C.; Agranoff, Dan; Edwards, Dylan R.; Friedland, Jon S.

doi:10.4049/jimmunol.0903811

Cited by 69 publications

(70 citation statements)

References 53 publications

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“…Doxycycline also suppressed TNF-a secretion, a key cytokine in the immune response to TB (7). TNF-a drives stromal cell MMP secretion via intercellular networks (22,26,35) and may also drive cachexia in TB (36), so doxycycline may have multiple immunomodulatory effects.…”

Section: Discussionmentioning

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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125

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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Section: Discussionmentioning

confidence: 99%

Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

Walker

Clark²,

Oni

et al. 2012

Am J Respir Crit Care Med

Self Cite

125

136

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“…Secretion of MMP-9 was the most readily detected, though the secretion of the other MMPs may not have been detected due to the relative insensitivity of casein zymography to detect MMP-1, -3 and -7 [19]. More recently, investigating central nervous system TB, we have found that monocyte-microglial cell networks upregulate MMP-1 and -3 [39].…”

Section: Mmps Driven By Intercellular Networkmentioning

confidence: 94%

“…In lymph node TB, both epithelioid macrophages and multinucleate giant cells express MMP-9 [37,38]. In CNS TB, MMP-1, MMP-3 and MMP-9 expression has been demonstrated in cerebral TB granulomas [39,40]. In addition, astrocytes are a significant source of MMP-9 [41].…”

Section: Defining the Mmps Involved In The Pathogenesis Of Tbmentioning

confidence: 99%

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Matrix metalloproteinases in tuberculosis

Elkington¹,

Ugarte-Gil²,

Friedland³

2011

Eur Respir J

117

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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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“…It is likely that numerous systemic diseases (such as Sjö gren syndrome) and their treatments (medications, head and neck radiation, chemotherapy) contribute significantly to salivary gland hypofunction. [3][4][5][6] Whole saliva is a mixed fluid that derives predominantly from 3 pairs of major salivary glands: the submandibular (SMG), the parotid, and the sublingual glands. Approximately 90% of total salivary volume results from the activity of these 3 pairs of glands, with the bulk of the remainder from minor salivary glands located at various oral mucosal sites.…”

Section: Introductionmentioning

confidence: 99%

Endocannabinoids mediate hyposalivation induced by inflammogens in the submandibular glands and hypothalamus

Prestifilippo¹,

Medina²,

Mohn³

et al. 2013

Archives of Oral Biology

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Mycobacterium tuberculosis Upregulates Microglial Matrix Metalloproteinase-1 and -3 Expression and Secretion via NF-κB– and Activator Protein-1–Dependent Monocyte Networks

Abstract: Material

Cited by 69 publications

References 53 publications

Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

Matrix metalloproteinases in tuberculosis

Endocannabinoids mediate hyposalivation induced by inflammogens in the submandibular glands and hypothalamus

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