Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFα, NFκB, p38 and caspase 8 dependent pathways

Green, Justin A.; Dholakia, Shruti; Janczar, Karolina; C, Ong; Moores, Rachel; Fry, J. F.; Elkington, Paul; Roncaroli, Federico; Friedland, Jon S.

doi:10.1186/1742-2094-8-46

Cited by 35 publications

(32 citation statements)

References 53 publications

(72 reference statements)

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“…NF-κB and HIF-1α interact to regulate innate immunity and inflammation. 9 10 NF-κB critically regulates MMP activity in TB infection of the central nervous system, 30 but has not been investigated in the context of hypoxia-driven MMP expression in TB infection. NF-κB is both directly affected by hypoxia and modulates HIF-1α expression as well as being regulated by prolyl hydroxylases.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia and tissue destruction in pulmonary TB

Belton

Brilha

Manavaki

et al. 2016

Thorax

Self Cite

140

115

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BackgroundIt is unknown whether lesions in human TB are hypoxic or whether this influences disease pathology. Human TB is characterised by extensive lung destruction driven by host matrix metalloproteinases (MMPs), particularly collagenases such as matrix metalloproteinase-1 (MMP-1).MethodsWe investigated tissue hypoxia in five patients with PET imaging using the tracer [18F]-fluoromisonidazole ([18F]FMISO) and by immunohistochemistry. We studied the regulation of MMP secretion in primary human cell culture model systems in normoxia, hypoxia, chemical hypoxia and by small interfering RNA (siRNA) inhibition.Results[18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe tissue hypoxia in man. Patlak analysis of dynamic PET data showed heterogeneous levels of hypoxia within and between patients. In Mycobacterium tuberculosis (M.tb)-infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 170-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine (DMOG), a small molecule inhibitor which stabilises the transcription factor hypoxia-inducible factor (HIF)-1α, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via intercellular networks regulated by TB. HIF-1α and NF-κB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1α accumulation even in normoxia. In human TB lung biopsies, epithelioid macrophages and multinucleate giant cells express HIF-1α. HIF-1α blockade, including by targeted siRNA, inhibited TB-driven MMP-1 gene expression and secretion.ConclusionsHuman TB lesions are severely hypoxic and M.tb drives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation.

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Section: Discussionmentioning

confidence: 99%

Hypoxia and tissue destruction in pulmonary TB

Belton

Brilha

Manavaki

et al. 2016

Thorax

Self Cite

140

115

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“…Inhibition of NF-kB using chemical inhibitors resulted in increased MMP-2 secretion in microglial cell lines, indicating that NF-kB negatively regulates MMP-2 secretion in these cells, with the p65 subunit expressed in biopsies of patients with central nervous system TB (71). NF-kB similarly regulates MMP-9 secretion in astrocytes (72).…”

Section: The Regulation Of Mmp Expression In Tbmentioning

confidence: 99%

Tuberculosis, Pulmonary Cavitation, and Matrix Metalloproteinases

Elkington

Friedland

2014

Am J Respir Crit Care Med

190

179

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Tuberculosis (TB), a chronic infectious disease of global importance, is facing the emergence of drug-resistant strains with few new drugs to treat the infection. Pulmonary cavitation, the hallmark of established disease, is associated with very high bacillary burden. Cavitation may lead to delayed sputum culture conversion, emergence of drug resistance, and transmission of the infection. The host immunological reaction to Mycobacterium tuberculosis is implicated in driving the development of TB cavities. TB is characterized by a matrix-degrading phenotype in which the activity of proteolytic matrix metalloproteinases (MMPs) is relatively unopposed by the specific tissue inhibitors of metalloproteinases. Proteases, in particular MMPs, secreted from monocyte-derived cells, neutrophils, and stromal cells, are involved in both cell recruitment and tissue damage and may cause cavitation. MMP activity is augmented by proinflammatory chemokines and cytokines, is tightly regulated by complex signaling paths, and causes matrix destruction. MMP concentrations are elevated in human TB and are closely associated with clinical and radiological markers of lung tissue destruction. Immunomodulatory therapies targeting MMPs in preclinical and clinical trials are potential adjuncts to TB treatment. Strategies targeting patients with cavitary TB have the potential to improve cure rates and reduce disease transmission.

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“…MMP-2, on the other hand, is regulated by TNF-a and p38-MAPK acting through NF-kB, but not AP-1 (Figure 2), and a caspase 8-dependent pathway. 35 Together, MMP regulation is not fully understood and varies between cell types in a contextdependent manner. 36,37 MMPs in brain and blood-brain barrier MMPs participate in many physiological and pathological processes in the brain and at the bloodbrain barrier ( Table 2).…”

Section: Function and Rolementioning

confidence: 99%

Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers

Rempe

Hartz

Bauer

2016

J Cereb Blood Flow Metab

520

422

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Matrix metalloproteinases are versatile endopeptidases with many different functions in the body in health and disease. In the brain, matrix metalloproteinases are critical for tissue formation, neuronal network remodeling, and blood-brain barrier integrity. Many reviews have been published on matrix metalloproteinases before, most of which focus on the two best studied matrix metalloproteinases, the gelatinases MMP-2 and MMP-9, and their role in one or two diseases. In this review, we provide a broad overview of the role various matrix metalloproteinases play in brain disorders. We summarize and review current knowledge and understanding of matrix metalloproteinases in the brain and at the bloodbrain barrier in neuroinflammation, multiple sclerosis, cerebral aneurysms, stroke, epilepsy, Alzheimer's disease, Parkinson's disease, and brain cancer. We discuss the detrimental effects matrix metalloproteinases can have in these conditions, contributing to blood-brain barrier leakage, neuroinflammation, neurotoxicity, demyelination, tumor angiogenesis, and cancer metastasis. We also discuss the beneficial role matrix metalloproteinases can play in neuroprotection and anti-inflammation. Finally, we address matrix metalloproteinases as potential therapeutic targets. Together, in this comprehensive review, we summarize current understanding and knowledge of matrix metalloproteinases in the brain and at the blood-brain barrier in brain disorders.

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Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFα, NFκB, p38 and caspase 8 dependent pathways

Cited by 35 publications

References 53 publications

Hypoxia and tissue destruction in pulmonary TB

Hypoxia and tissue destruction in pulmonary TB

Tuberculosis, Pulmonary Cavitation, and Matrix Metalloproteinases

Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers

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