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      Monocyte Adhesion, Migration, and Extracellular Matrix Breakdown Are Regulated by Integrin αVβ3 in Mycobacterium tuberculosis Infection

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          Abstract

          In tuberculosis (TB), the innate inflammatory immune response drives tissue destruction, morbidity, and mortality. Monocytes secrete matrix metalloproteinases (MMPs), which have key roles in local tissue destruction and cavitation. We hypothesized that integrin signaling might regulate monocyte MMP secretion in pulmonary TB during cell adhesion to the extracellular matrix (ECM). Adhesion to type I collagen and fibronectin by Mycobacterium tuberculosis–stimulated monocytes increased MMP-1 gene expression by 2.6-fold and 4.3-fold respectively, and secretion by 60% (from 1208.1 ± 186 to 1934.4 ± 135 pg/ml; p < 0.0001) and 63% (1970.3 ± 95 pg/ml; p < 0.001). MMP-10 secretion increased by 90% with binding to type I collagen and 55% with fibronectin, whereas MMP-7 increased 57% with collagen. The ECM did not affect the secretion of tissue inhibitors of metalloproteinases-1 or -2. Integrin αVβ3 surface expression was specifically upregulated in stimulated monocytes and was further increased after adhesion to type I collagen. Binding of either β3 or αV integrin subunits increased MMP-1/10 secretion in M. tuberculosis–stimulated monocytes. In a cohort of TB patients, significantly increased integrin β3 mRNA accumulation in induced sputum was detected, to our knowledge, for the first time, compared with control subjects ( p < 0.05). Integrin αVβ3 colocalized with areas of increased and functionally active MMP-1 on infected monocytes, and αVβ3 blockade markedly decreased type I collagen breakdown, and impaired both monocyte adhesion and leukocyte migration in a transwell system ( p < 0.0001). In summary, our data demonstrate that M. tuberculosis stimulation upregulates integrin αVβ3 expression on monocytes, which upregulates secretion of MMP-1 and -10 on adhesion to the ECM. This leads to increased monocyte recruitment and collagenase activity, which will drive inflammatory tissue damage.

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          Most cited references36

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          Getting to the site of inflammation: the leukocyte adhesion cascade updated.

          Neutrophil recruitment, lymphocyte recirculation and monocyte trafficking all require adhesion and transmigration through blood-vessel walls. The traditional three steps of rolling, activation and firm adhesion have recently been augmented and refined. Slow rolling, adhesion strengthening, intraluminal crawling and paracellular and transcellular migration are now recognized as separate, additional steps. In neutrophils, a second activation pathway has been discovered that does not require signalling through G-protein-coupled receptors and the signalling steps leading to integrin activation are beginning to emerge. This Review focuses on new aspects of one of the central paradigms of inflammation and immunity--the leukocyte adhesion cascade.
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            Extracellular matrix degradation and remodeling in development and disease.

            The extracellular matrix (ECM) serves diverse functions and is a major component of the cellular microenvironment. The ECM is a highly dynamic structure, constantly undergoing a remodeling process where ECM components are deposited, degraded, or otherwise modified. ECM dynamics are indispensible during restructuring of tissue architecture. ECM remodeling is an important mechanism whereby cell differentiation can be regulated, including processes such as the establishment and maintenance of stem cell niches, branching morphogenesis, angiogenesis, bone remodeling, and wound repair. In contrast, abnormal ECM dynamics lead to deregulated cell proliferation and invasion, failure of cell death, and loss of cell differentiation, resulting in congenital defects and pathological processes including tissue fibrosis and cancer. Understanding the mechanisms of ECM remodeling and its regulation, therefore, is essential for developing new therapeutic interventions for diseases and novel strategies for tissue engineering and regenerative medicine.
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              Structure and function of matrix metalloproteinases and TIMPs.

              Matrix metalloproteinases (MMPs), also called matrixins, function in the extracellular environment of cells and degrade both matrix and non-matrix proteins. They play central roles in morphogenesis, wound healing, tissue repair and remodelling in response to injury, e.g. after myocardial infarction, and in progression of diseases such as atheroma, arthritis, cancer and chronic tissue ulcers. They are multi-domain proteins and their activities are regulated by tissue inhibitors of metalloproteinases (TIMPs). This review introduces the members of the MMP family and discusses their domain structure and function, proenyme activation, the mechanism of inhibition by TIMPs and their significance in physiology and pathology.
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                Author and article information

                Journal
                J Immunol
                J. Immunol
                jimmunol
                jimmunol
                JI
                The Journal of Immunology Author Choice
                AAI
                0022-1767
                1550-6606
                1 August 2017
                23 June 2017
                : 199
                : 3
                : 982-991
                Affiliations
                [* ]Department of Infectious Diseases and Immunity, Imperial College London, London W12 0NN, United Kingdom;
                []Centre for Inflammation and Tissue Repair, Respiratory Medicine, University College London, London WC1E 6JF, United Kingdom; and
                []Centre for Molecular Medicine, University College London, London WC1E 6JF, United Kingdom
                Author notes
                Address correspondence and reprint requests to Prof. Jon S. Friedland, Department of Infectious Diseases and Immunity, Imperial College London, Eighth Floor Commonwealth Building, Hammersmith Campus, Du Cane Road, London W12 0NN, U.K. E-mail address: j.friedland@ 123456imperial.ac.uk
                Author information
                http://orcid.org/0000-0003-2608-4444
                http://orcid.org/0000-0001-7789-9649
                http://orcid.org/0000-0002-7307-169X
                Article
                ji_1700128
                10.4049/jimmunol.1700128
                5523580
                28646039
                764c4da8-5a4b-47bc-904b-fed800e3811a
                Copyright © 2017 The Authors

                This article is distributed under the terms of the CC BY 4.0 Unported license .

                History
                : 24 January 2017
                : 02 May 2017
                Page count
                Figures: 7, Equations: 0, References: 35, Pages: 10
                Categories
                Infectious Disease and Host Response

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