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      Galectin-3 enhances monocyte-derived macrophage efferocytosis of apoptotic granulocytes in asthma

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          Abstract

          Background

          Galectin-3 is a 32 kDa protein secreted by macrophages involved in processes such as cell activation, chemotaxis and phagocytosis. Galectin-3 has previously been shown to improve the ability of airway macrophages to ingest apoptotic cells (efferocytosis) in chronic obstructive pulmonary disease (COPD) and may be of interest in non-eosinophilic asthma (NEA) which is also characterised by impaired efferocytosis. It was hypothesised that the addition of exogenous galectin-3 to monocyte-derived macrophages (MDMs) derived from donors with NEA would enhance their ability to engulf apoptotic granulocytes.

          Methods

          Eligible non-smoking adults with asthma ( n = 19), including 7 with NEA and healthy controls ( n = 10) underwent a clinical assessment, venepuncture and sputum induction. MDMs were co-cultured with apoptotic granulocytes isolated from healthy donors with or without exogenous recombinant galectin-3 (50 μg/mL) and efferocytosis was assessed by flow cytometry. Galectin-3 expression and localisation in MDMs was visualised by immunofluorescence staining and fluorescence microscopy. Galectin-3, interleukin (IL)-6 and CXCL8 secretion were measured in cell culture supernatants by ELISA and cytometric bead array.

          Results

          Baseline efferocytosis (mean (±standard deviation)) was lower in participants with asthma (33.2 (±17.7)%) compared with healthy controls (45.3 (±15.9)%; p = 0.081). Efferocytosis did not differ between the participants with eosinophilic asthma (EA) (31.4 (±19.2)%) and NEA (28.7 (±21.5)%; p = 0.748). Addition of galectin-3 significantly improved efferocytosis in asthma, particularly in NEA (37.8 (±18.1)%) compared with baseline (30.4 (±19.7)%; p = 0.012). Efferocytosis was not associated with any of the clinical outcomes but was negatively correlated with sputum macrophage numbers (Spearman r = − 0.671; p = 0.017). Galectin-3 was diffusely distributed in most MDMs but formed punctate structures in 5% of MDMs. MDM galectin-3 secretion was lower in asthma (9.99 (2.67, 15.48) ng/mL) compared with the healthy controls (20.72 (11.28, 27.89) ng/mL; p = 0.044) while IL-6 and CXCL8 levels were similar.

          Conclusions

          Galectin-3 modulates macrophage function in asthma, indicating a potential role for galectin-3 to reverse impaired efferocytosis in NEA.

          Electronic supplementary material

          The online version of this article (10.1186/s12931-018-0967-9) contains supplementary material, which is available to authorized users.

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          Most cited references25

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          Asthma

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            Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986.

            Chronic obstructive pulmonary disease (COPD) and asthma are the major causes of pulmonary disability in the United States, with at least 10 million Americans suffering form COPD and up to 5% of the population afflicted with asthma. Over the past 20 years, major strides have been made in our understanding of the pathophysiology of these disorders, although there are still large gaps in our knowledge. While a number of position papers and statements have been promulgated by the American Thoracic Society concerning various aspects of the diagnosis and treatment of COPD and asthma, it was felt that a review of the overall topic was timely. This statement represents the combined efforts of a Task Group appointed by the Scientific Assemble of Clinical Problems of the American Thoracic Society to accomplish this task. Clearly, we could not cover every aspect of this broad topic nor even provide a detailed review of those areas addressed. We elected instead to concentrate on clinically relevant topics and to provide sufficient data to be useful as a guide as well as to include selected, but in no was exhaustive, references. The first two chapters define the entities and set forth recommendations for diagnosis, hospital admission, and discharge. The remaining four chapters critically review the various facets of therapy. We have noted controversial areas and those were conclusive experimental data are not yet available. In these situations, the committee often decided to take a position on one side or the other based upon the best available information.
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              Galectin-3, a marker for vacuole lysis by invasive pathogens.

              Shigella bacteria invade macrophages and epithelial cells and following internalization lyse the phagosome and escape to the cytoplasm. Galectin-3, an abundant protein in macrophages and epithelial cells, belongs to a family of beta-galactoside-binding proteins, the galectins, with many proposed functions in immune response, development, differentiation, cancer and infection. Galectins are synthesized as cytosolic proteins and following non-classical secretion bind extracellular beta-galactosides. Here we analysed the localization of galectin-3 following entry of Shigella into the cytosol and detected a striking phenomenon. Very shortly after bacterial invasion, intracellular galectin-3 accumulated in structures in vicinity to internalized bacteria. By using immuno-electron microscopy analysis we identified galectin-3 in membranes localized in the phagosome and in tubules and vesicles that derive from the endocytic pathway. We also demonstrated that the binding of galectin-3 to host N-acetyllactosamine-containing glycans, was required for forming the structures. Accumulation of the structures was a type three secretion system-dependent process. More specifically, existence of structures was strictly dependent upon lysis of the phagocytic vacuole and could be shown also by Gram-positive Listeria and Salmonella sifA mutant. We suggest that galectin-3-containing structures may serve as a potential novel tool to spot vacuole lysis.
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                Author and article information

                Contributors
                melanie.erriah@uon.edu.au
                kavita.pabreja@newcastle.edu.au
                michael.fricker@newcastle.edu.au
                katherine.baines@newcastle.edu.au
                l.donnelly@imperial.ac.uk
                johan.bylund@gu.se
                anna.karlsson@gu.se
                jodie.simpson@newcastle.edu.au
                Journal
                Respir Res
                Respir. Res
                Respiratory Research
                BioMed Central (London )
                1465-9921
                1465-993X
                3 January 2019
                3 January 2019
                2019
                : 20
                : 1
                Affiliations
                [1 ]ISNI 0000 0000 8831 109X, GRID grid.266842.c, Priority Research Centre for Healthy Lungs, , The University of Newcastle, ; Newcastle, NSW Australia
                [2 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Airway Disease Section, National Heart and Lung Institute, , Imperial College London, ; London, UK
                [3 ]ISNI 0000 0000 9919 9582, GRID grid.8761.8, Department of Oral Microbiology and Immunology, , Sahlgrenska Academy at the University of Gothenburg, ; Gothenburg, Sweden
                [4 ]ISNI 0000 0000 9919 9582, GRID grid.8761.8, Department of Rheumatology and Inflammation Research, , Sahlgrenska Academy at the University of Gothenburg, ; Gothenburg, Sweden
                Article
                967
                10.1186/s12931-018-0967-9
                6318889
                30606211
                ba2c1a1e-b6f1-46b8-8b7e-dced06770bd9
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 12 September 2018
                : 16 December 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;
                Award ID: APP1103733
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Respiratory medicine
                asthma,galectin-3,macrophage,neutrophil,efferocytosis,inflammation
                Respiratory medicine
                asthma, galectin-3, macrophage, neutrophil, efferocytosis, inflammation

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