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      Dendritic Cell-Mediated Phagocytosis but Not Immune Activation Is Enhanced by Plasmin

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          Abstract

          Removal of dead cells in the absence of concomitant immune stimulation is essential for tissue homeostasis. We recently identified an injury-induced protein misfolding event that orchestrates the plasmin-dependent proteolytic degradation of necrotic cells. As impaired clearance of dead cells by the innate immune system predisposes to autoimmunity, we determined whether plasmin could influence endocytosis and immune cell stimulation by dendritic cells – a critical cell that links the innate and adaptive immune systems. We find that plasmin generated on the surface of necrotic cells enhances their phagocytic removal by human monocyte-derived dendritic cells. Plasmin also promoted phagocytosis of protease-resistant microparticles by diverse mouse dendritic cell sub-types both in vitro and in vivo. Together with an increased phagocytic capacity, plasmin-treated dendritic cells maintain an immature phenotype, exhibit reduced migration to lymph nodes, increase their expression/release of the immunosuppressive cytokine TGF-β, and lose their capacity to mount an allogeneic response. Collectively, our findings support a novel role for plasmin formed on dead cells and other phagocytic targets in maintaining tissue homeostasis by increasing the phagocytic function of dendritic cells while simultaneously decreasing their immunostimulatory capacity consistent with producing an immunosuppressive state.

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          Most cited references36

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          Decoding cell death signals in inflammation and immunity.

          Dying cells release and expose at their surface molecules that signal to the immune system. We speculate that combinations of these molecules determine the route by which dying cells are engulfed and the nature of the immune response that their death elicits. 2010 Elsevier Inc. All rights reserved.
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            Molecular mechanisms of late apoptotic/necrotic cell clearance.

            Phagocytosis serves as one of the key processes involved in development, maintenance of tissue homeostasis, as well as in eliminating pathogens from an organism. Under normal physiological conditions, dying cells (e.g., apoptotic and necrotic cells) and pathogens (e.g., bacteria and fungi) are rapidly detected and removed by professional phagocytes such as macrophages and dendritic cells (DCs). In most cases, specific receptors and opsonins are used by phagocytes to recognize and bind their target cells, which can trigger the intracellular signalling events required for phagocytosis. Depending on the type of target cell, phagocytes may also release both immunomodulatory molecules and growth factors to orchestrate a subsequent immune response and wound healing process. In recent years, evidence is growing that opsonins and receptors involved in the removal of pathogens can also aid the disposal of dying cells at all stages of cell death, in particular plasma membrane-damaged cells such as late apoptotic and necrotic cells. This review provides an overview of the molecular mechanisms and the immunological outcomes of late apoptotic/necrotic cell removal and highlights the striking similarities between late apoptotic/necrotic cell and pathogen clearance.
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              A plasminogen-activating protease specifically controls the development of primary pneumonic plague.

              Primary pneumonic plague is transmitted easily, progresses rapidly, and causes high mortality, but the mechanisms by which Yersinia pestis overwhelms the lungs are largely unknown. We show that the plasminogen activator Pla is essential for Y. pestis to cause primary pneumonic plague but is less important for dissemination during pneumonic plague than during bubonic plague. Experiments manipulating its temporal expression showed that Pla allows Y. pestis to replicate rapidly in the airways, causing a lethal fulminant pneumonia; if unexpressed, inflammation is aborted, and lung repair is activated. Inhibition of Pla expression prolonged the survival of animals with the disease, offering a therapeutic option to extend the period during which antibiotics are effective.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                1 July 2015
                2015
                : 10
                : 7
                : e0131216
                Affiliations
                [1 ]Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct, Melbourne, 3004, Victoria Australia
                [2 ]Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3181, Australia
                [3 ]Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Melbourne, 3004, Victoria, Australia
                [4 ]Department of Medicine, Monash University, Alfred Medical Research and Education Precinct, Melbourne, 3004, Victoria, Australia
                [5 ]Department of Allergy, Immunology and Respiratory Medicine, Alfred Medical Research and Education Precinct, Melbourne, 3004, Victoria, Australia
                University of California San Francisco, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RJB ALS MP RLM. Performed the experiments: RJB ALS AELA MF YYK RF NAM. Analyzed the data: RJB ALS AELA AS MF YYK MP RLM. Contributed reagents/materials/analysis tools: RLM NAM MP. Wrote the paper: RJB ALS MP RLM.

                [¤]

                Current Address: Radbound University Medical Center, Department of Medical Microbiology, 525GA Nijmegen, The Netherlands

                ‡ ALS, MP and RLM are joint senior authors on this work.

                Article
                PONE-D-15-05967
                10.1371/journal.pone.0131216
                4488505
                26132730
                85bd1c03-45b9-46f5-9588-381f02cab40d
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 10 February 2015
                : 29 May 2015
                Page count
                Figures: 7, Tables: 0, Pages: 19
                Funding
                This study was supported in part by a grant awarded to R.L.M. and A.L.S. from the National Health and Medical Research Council of Australia, grant #606659. R.L.M. and M.P. are also recipients of National Health and Medical Research Council Principal Research Fellowship (R.L.M.; #10441520 or a Senior Research Fellowship (M.P.; #1059409).
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                Research Article
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