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      Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype

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          Abstract

          Ablation of the immunomodulator osteopontin correlates with reduced fibrosis and improved muscle strength in Duchenne muscular dystrophy models. Here, Capote et al. show that osteopontin ablation skews dystrophic macrophages toward a pro-regenerative phenotype, leading to improved and sustained muscle mass and strength in long-term functional testing.

          Abstract

          In the degenerative disease Duchenne muscular dystrophy, inflammatory cells enter muscles in response to repetitive muscle damage. Immune factors are required for muscle regeneration, but chronic inflammation creates a profibrotic milieu that exacerbates disease progression. Osteopontin (OPN) is an immunomodulator highly expressed in dystrophic muscles. Ablation of OPN correlates with reduced fibrosis and improved muscle strength as well as reduced natural killer T (NKT) cell counts. Here, we demonstrate that the improved dystrophic phenotype observed with OPN ablation does not result from reductions in NKT cells. OPN ablation skews macrophage polarization toward a pro-regenerative phenotype by reducing M1 and M2a and increasing M2c subsets. These changes are associated with increased expression of pro-regenerative factors insulin-like growth factor 1, leukemia inhibitory factor, and urokinase-type plasminogen activator. Furthermore, altered macrophage polarization correlated with increases in muscle weight and muscle fiber diameter, resulting in long-term improvements in muscle strength and function in mdx mice. These findings suggest that OPN ablation promotes muscle repair via macrophage secretion of pro-myogenic growth factors.

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          Most cited references51

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          Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity.

          Cell-mediated (type-1) immunity is necessary for immune protection against most intracellular pathogens and, when excessive, can mediate organ-specific autoimmune destruction. Mice deficient in Eta-1 (also called osteopontin) gene expression have severely impaired type-1 immunity to viral infection [herpes simplex virus-type 1 (KOS strain)] and bacterial infection (Listeria monocytogenes) and do not develop sarcoid-type granulomas. Interleukin-12 (IL-12) and interferon-gamma production is diminished, and IL-10 production is increased. A phosphorylation-dependent interaction between the amino-terminal portion of Eta-1 and its integrin receptor stimulated IL-12 expression, whereas a phosphorylation-independent interaction with CD44 inhibited IL-10 expression. These findings identify Eta-1 as a key cytokine that sets the stage for efficient type-1 immune responses through differential regulation of macrophage IL-12 and IL-10 cytokine expression.
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            Macrophage phenotypes during tissue repair.

            Mp are crucial for tissue repair and regeneration but can also contribute to tissue damage and fibrosis. Mp can adopt a variety of functional phenotypes in response to different stimuli; two of the best-characterized in vitro phenotypes are a proinflammatory "M1" phenotype, produced by exposure to IFN-γ and TNF-α, and an anti-inflammatory "M2a" phenotype, produced by IL-4 or IL-13. M2a Mp are frequently termed "wound healing" Mp, as they express factors that are important for tissue repair. This review will summarize current knowledge of Mp phenotypes during tissue repair and will argue that these in vivo Mp populations are heterogeneous and temporally regulated and do not conform to existing, in vitro-defined M1 or M2 phenotypes. Mp during the early stages of tissue repair exhibit a more proinflammatory phenotype than their later counterparts, which in turn may exhibit some M2a-associated characteristics. However, phenotypic markers that appear to be coregulated in cultured Mp can be expressed independently of each other in vivo. Additionally, M1- and M2-associated markers may be expressed simultaneously by actual tissue-repair Mp. Improved understanding of Mp phenotypes and their regulation may assist in generation of novel therapies based on manipulating Mp function to improve healing.
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              Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy.

              Duchenne muscular dystrophy (DMD) is the most common, lethal, muscle-wasting disease of childhood. Previous investigations have shown that muscle macrophages may play an important role in promoting the pathology in the mdx mouse model of DMD. In the present study, we investigate the mechanism through which macrophages promote mdx dystrophy and assess whether the phenotype of the macrophages changes between the stage of peak muscle necrosis (4 weeks of age) and muscle regeneration (12 weeks). We find that 4-week-old mdx muscles contain a population of pro-inflammatory, classically activated M1 macrophages that lyse muscle in vitro by NO-mediated mechanisms. Genetic ablation of the iNOS gene in mdx mice also significantly reduces muscle membrane lysis in 4-week-old mdx mice in vivo. However, 4-week mdx muscles also contain a population of alternatively activated, M2a macrophages that express arginase. In vitro assays show that M2a macrophages reduce lysis of muscle cells by M1 macrophages through the competition of arginase in M2a cells with iNOS in M1 cells for their common, enzymatic substrate, arginine. During the transition from the acute peak of mdx pathology to the regenerative stage, expression of IL-4 and IL-10 increases, either of which can deactivate the M1 phenotype and promote activation of a CD163+, M2c phenotype that can increase tissue repair. Our findings further show that IL-10 stimulation of macrophages activates their ability to promote satellite cell proliferation. Deactivation of the M1 phenotype is also associated with a reduced expression of iNOS, IL-6, MCP-1 and IP-10. Thus, these results show that distinct subpopulations of macrophages can promote muscle injury or repair in muscular dystrophy, and that therapeutic interventions that affect the balance between M1 and M2 macrophage populations may influence the course of muscular dystrophy.
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                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                jcb
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                25 April 2016
                : 213
                : 2
                : 275-288
                Affiliations
                [1 ]Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095
                [2 ]Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095
                [3 ]Molecular, Cellular, and Integrative Physiology Interdepartmental PhD Program, University of California, Los Angeles, Los Angeles, CA 90095
                [4 ]Center for Duchenne Muscular Dystrophy at UCLA, Los Angeles, CA 90095
                [5 ]Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610
                [6 ]Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611
                [7 ]Wellstone Muscular Dystrophy Center, University of Florida, Gainesville, FL 32610
                Author notes
                Correspondence to Melissa J. Spencer: mspencer@ 123456mednet.ucla.edu ; or Irina Kramerova: ikramero@ 123456ucla.edu

                S. Vetrone’s present address is Dept. of Biology, Whittier College, Whittier, CA 90608.

                Article
                201510086
                10.1083/jcb.201510086
                5084275
                27091452
                15c97f4d-c3dd-4b80-a61e-ab9b372a099a
                © 2016 Capote et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 21 October 2015
                : 15 March 2016
                Funding
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases http://dx.doi.org/10.13039/100000069
                Award ID: U54AR052646
                Award ID: NIAMS-P30AR057230-01
                Funded by: National Institutes of Health http://dx.doi.org/10.13039/100000002
                Award ID: RO1 AR046911
                Funded by: Parent Project Muscular Dystrophy http://dx.doi.org/10.13039/100005693
                Funded by: Muscular Dystrophy Association http://dx.doi.org/10.13039/100005202
                Funded by: National Institutes of Health http://dx.doi.org/10.13039/100000002
                Award ID: P30 CA016042
                Award ID: 5P30 AI028697
                Categories
                Research Articles
                Article

                Cell biology
                Cell biology

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