title: TRPV4 Mechanosensitive Ion Channel Regulates Lipopolysaccharide-Stimulated Macrophage Phagocytosis.
abstract: Macrophage phagocytosis of particles and pathogens is an essential aspect of innate host defense. Phagocytic function requires cytoskeletal rearrangements that depend on the interaction between macrophage surface receptors, particulates/pathogens, and the extracellular matrix. In the present study we determine the role of a mechanosensitive ion channel, transient receptor potential vanilloid 4 (TRPV4), in integrating the LPS and matrix stiffness signals to control macrophage phenotypic change for host defense and resolution from lung injury. We demonstrate that active TRPV4 mediates LPS-stimulated murine macrophage phagocytosis of nonopsonized particles (Escherichia coli) in vitro and opsonized particles (IgG-coated latex beads) in vitro and in vivo in intact mice. Intriguingly, matrix stiffness in the range seen in inflamed or fibrotic lung is required to sensitize the TRPV4 channel to mediate the LPS-induced increment in macrophage phagocytosis. Furthermore, TRPV4 is required for the LPS induction of anti-inflammatory/proresolution cytokines. These findings suggest that signaling through TRPV4, triggered by changes in extracellular matrix stiffness, cooperates with LPS-induced signals to mediate macrophage phagocytic function and lung injury resolution. These mechanisms are likely to be important in regulating macrophage function in the context of pulmonary infection and fibrosis.
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195; and.
authors.forename: Rachel G
authors.initials: RG
authors.lastname: Scheraga
authors.affiliation: Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195; and.
authors.forename: Susamma
authors.initials: S
authors.lastname: Abraham
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Niese
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195; and.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Southern
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Grove
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195; and.
authors.forename: R Duncan
authors.identifier: http://orcid.org/0000-0002-2625-8750
authors.initials: RD
authors.lastname: Hite
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Christine
authors.identifier: http://orcid.org/0000-0002-6745-9487
authors.initials: C
authors.lastname: McDonald
authors.affiliation: Department of Immunology, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hamilton
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195; and olmanm@ccf.org.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Olman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000276:immunology / Q000382:microbiology; D005109:Extracellular Matrix / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D055370:Lung Injury / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology*; D055595:Mechanical Phenomena; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D010587:Phagocytosis / Q000276:immunology*; D011658:Pulmonary Fibrosis / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D050916:TRPV Cation Channels / Q000276:immunology*
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse