title: Impact of the FcgammaII-receptor on quartz uptake and inflammatory response by alveolar macrophages.
abstract: The inflammatory response following particle inhalation is described as a key event in the development of lung diseases, e.g., fibrosis and cancer. The essential role of alveolar macrophages (AM) in the pathogenicity of particles through their functions in lung clearance and mediation of inflammation is well known. However, the molecular mechanisms and direct consequences of particle uptake are still unclear. Inhibition of different classic phagocytosis receptors by flow cytometry shows a reduction of the dose-dependent quartz particle (DQ12) uptake in the rat AM cell line NR8383. Thereby the strongest inhibitory effect was observed by blocking the FcgammaII-receptor (FcgammaII-R). Fluorescence immunocytochemistry, demonstrating FcgammaII-R clustering at particle binding sites as well as transmission electron microscopy, visualizing zippering mechanism-like morphological changes, confirmed the role of the FcgammaII-R in DQ12 phagocytosis. FcgammaII-R participation in DQ12 uptake was further strengthened by the quartz-induced activation of the Src-kinase Lyn, the phospho-tyrosine kinases Syk (spleen tyrosine kinase) and PI3K (phosphatidylinositol 3-kinase), as shown by Western blotting. Activation of the small GTPases Rac1 and Cdc42, shown by immunoprecipitation, as well as inhibition of tyrosine kinases, GTPases, or Rac1 provided further support for the role of the FcgammaII-R. Consistent with the uptake results, FcgammaII-R activation with its specific ligand caused a similar generation of reactive oxygen species and TNF-alpha release as observed after treatment with DQ12. In conclusion, our results indicate a major role of FcgammaII-R and its downstream signaling cascade in the phagocytosis of quartz particles in AM as well as in the associated generation and release of inflammatory mediators.
authors.affiliation: Particle Research, Institut für Umweltmedizinische Forschung at the Heinrich Heine University, Auf'm Hennekamp 50, 40225 Düsseldorf, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Haberzettl
authors.forename: Roel P F
authors.initials: RP
authors.lastname: Schins
authors.forename: Doris
authors.initials: D
authors.lastname: Höhr
authors.forename: Verena
authors.initials: V
authors.lastname: Wilhelmi
authors.forename: Paul J A
authors.initials: PJ
authors.lastname: Borm
authors.forename: Catrin
authors.initials: C
authors.lastname: Albrecht
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D005434:Flow Cytometry; D007249:Inflammation / Q000503:physiopathology*; D008148:Lovastatin / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000502:physiology*; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology*; D011069:Poly I / Q000494:pharmacology; D011134:Polysaccharides / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D011791:Quartz / Q000378:metabolism*; D051381:Rats; D017452:Receptors, IgG / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D000634:Aminoquinolines; C487513:NSC 23766; D011134:Polysaccharides; D011743:Pyrimidines; D017452:Receptors, IgG; D011791:Quartz; D011069:Poly I; C007789:fucoidan; D008148:Lovastatin; D011505:Protein-Tyrosine Kinases; D020559:Monomeric GTP-Binding Proteins