Matrix Metalloproteinase-19 Deficiency Promotes Tenascin-C Accumulation and Allergen-Induced Airway Inflammation

Guéders, Maud; Hirst, Stuart J John; Quesada-Calvo, Florence; Paulissen, Geneviève; Hacha, Jonathan; Gilles, Christine; Gosset, Philippe; Louis, Renaud; Foidart, Jean-Michel; López-Otı́n, Carlos; Noël, Agnès; Cataldo, Didier

doi:10.1165/rcmb.2008-0426oc

Cited by 30 publications

(27 citation statements)

References 52 publications

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“…Similar to our observation in MMP19 2/2 mice exposed to bleomycin, exaggerated tenascin C accumulation was observed in MMP-19-deficient mice exposed to a murine model of asthma. Interestingly, the MMP-19-deficient mice demonstrated exaggerated allergen-induced airway eosinophilic inflammation and a shift toward Th2-driven inflammation (41), which is consistent with the effects of PTGS2 on dendritic cells (42). The up-regulation and localization of MMP19 to the regressing keloid center in skin scarring lesions (43) also support a putative antifibrotic role of MMP-19.…”

Section: Discussionmentioning

confidence: 54%

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Kovkarova-Naumovski²,

Jara³

et al. 2012

Am J Respir Crit Care Med

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by epithelial phenotypic changes and fibroblast activation. Based on the temporal heterogeneity of IPF, we hypothesized that hyperplastic alveolar epithelial cells regulate the fibrotic response. Objectives: To identify novel mediators of fibrosis comparing the transcriptional signature of hyperplastic epithelial cells and conserved epithelial cells in the same lung. Methods: Laser capture microscope and microarrays analysis were used to identify differentially expressed genes in IPF lungs. Bleomycininduced lung fibrosis was evaluated in Mmp19-deficient and wild-type (WT) mice. The role of matrix metalloproteinase (MMP)-19 was additionally studied by transfecting the human MMP19 in alveolar epithelial cells. Measurements and Main Results: Laser capture microscope followed by microarray analysis revealed a novel mediator, MMP-19, in hyperplastic epithelial cells adjacent to fibrotic regions. Mmp19 2/2 mice showed a significantly increased lung fibrotic response to bleomycin compared with WT mice. A549 epithelial cells transfected with human MMP19 stimulated wound healing and cell migration, whereas silencing MMP19 had the opposite effect. Gene expression microarray of transfected A549 cells showed that PTGS2 (prostaglandin-endoperoxide synthase 2) was one of the highly induced genes. PTGS2 was overexpressed in IPF lungs and colocalized with MMP-19 in hyperplastic epithelial cells. In WT mice, PTGS2 was significantly increased in bronchoalveolar lavage and lung tissues after bleomycin-induced fibrosis, but not in Mmp19 2/2 mice. Inhibition of Mmp-19 by siRNA resulted in inhibition of Ptgs2 at mRNA and protein levels. Conclusions: Up-regulation of MMP19 induced by lung injury may play a protective role in the development of fibrosis through the induction of PTGS2.

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Section: Discussionmentioning

confidence: 54%

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Kovkarova-Naumovski²,

Jara³

et al. 2012

Am J Respir Crit Care Med

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“…Additionally, proteinases emerge as potential mediators in this airway disease associated with important tissue remodeling. Among them, several individual matrix metalloproteinases (MMPs) have been studied in asthma (9,10) and have been reported to play either a protective or an inducer role in the generation of experimentally induced asthma in murine models (9)(10)(11)(12)(13)(14). Three members of the related a disintegrin and metalloproteinases (ADAM) family, ADAM-8, ADAM-10 and ADAM-33, have also been linked to asthma (15)(16)(17).…”

mentioning

confidence: 99%

“…These murine experimental models, based on allergen challenge with either OVA (10) or house dust mite (HDM) (29), mimic the main features of human asthma, *Laboratory of Tumor and Developmental Biology, Interdisciplinary Group of Applied Genoproteomics-Cancer (GIGA-Cancer), University of Liège and University Hospital of Liège, 4000 Liège, Belgium; † Interdisciplinary Group of Applied Genoproteomics-3I (GIGA-I3), University of Liège (Centre Hospitalier Universitaire Liege), 4000 Liège, Belgium; and including airway inflammation. In this study, we provide, to our knowledge, the first experimental evidence that Adamts12 deficiency exacerbates allergen-induced inflammation and airway responsiveness by inducing a Th2 inflammation.…”

mentioning

confidence: 99%

Control of Allergen-Induced Inflammation and Hyperresponsiveness by the Metalloproteinase ADAMTS-12

Paulissen

Hour

Rocks

et al. 2012

The Journal of Immunology

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A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) constitute a family of endopeptidases related to matrix metalloproteinases. These proteinases have been largely implicated in tissue remodeling associated with pathological processes. Among them, ADAMTS12 was identified as an asthma-associated gene in a human genome screening program. However, its functional implication in asthma is not yet documented. The present study aims at investigating potential ADAMTS-12 functions in experimental models of allergic airways disease. Two different in vivo protocols of allergen-induced airways disease were applied to the recently generated Adamts12-deficient mice and corresponding wild-type mice. In this study, we provide evidence for a protective effect of ADAMTS-12 against bronchial inflammation and hyperresponsiveness. In the absence of Adamts12, challenge with different allergens (OVA and house dust mite) led to exacerbated eosinophilic inflammation in the bronchoalveolar lavage fluid and in lung tissue, along with airway dysfunction assessed by increased airway responsiveness following methacholine exposure. Furthermore, mast cell counts and ST2 receptor and IL-33 levels were higher in the lungs of allergen-challenged Adamts12-deficient mice. The present study provides, to our knowledge, the first experimental evidence for a contribution of ADAMTS-12 as a key mediator in airways disease, interfering with immunological processes leading to inflammation and airway hyperresponsiveness.

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“…In contrast, MMP-19 null mice exhibited elevated tenascin-C protein during a model of asthma, indicating that MMP-19 may prevent the accumulation of tenascin-C. 193 Tenascin-C is also susceptible to proteolytic degradation by MMPs-1, 2, 3 and 7 in vitro with the majority of MMP cleavage sites located within the alternatively spliced region of the protein, making long tenascin-C isoforms more susceptible to fragmentation than shorter isoforms. 97 MMP-7 cleaves all tenascin-C isoforms by removing the 16 kDa N-terminal knob, but it also digests FNIII A3-D within the alternatively spliced region; its ability to digest AD1 and AD2 is not yet known.…”

Section: Assembly Of Tenascin-c Into a Fibrillar Matrixmentioning

confidence: 99%

Tenascin-C: Form versus function

Giblin

Midwood²

2014

Cell Adhesion & Migration

195

233

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Matrix Metalloproteinase-19 Deficiency Promotes Tenascin-C Accumulation and Allergen-Induced Airway Inflammation

Cited by 30 publications

References 52 publications

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

Control of Allergen-Induced Inflammation and Hyperresponsiveness by the Metalloproteinase ADAMTS-12

Tenascin-C: Form versus function

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