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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/L1137    most recent 00261.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Haberzettl, P. Articles by Albrecht, C. PubMed PubMed Citation Articles by Haberzettl, P. Articles by Albrecht, C.

Impact of the FcII-receptor on quartz uptake and inflammatory response by alveolar macrophages

¹Particle Research, Institut für Umweltmedizinische Forschung at the Heinrich Heine University, Düsseldorf, Germany; and ²Centre of Expertise in Life Sciences, Hogeschool Zuyd, Heerlen, The Netherlands

Submitted 6 July 2007 ; accepted in final form 30 March 2008

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 FcII-receptor (FcII-R). Fluorescence immunocytochemistry, demonstrating FcII-R clustering at particle binding sites as well as transmission electron microscopy, visualizing zippering mechanism-like morphological changes, confirmed the role of the FcII-R in DQ12 phagocytosis. FcII-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 FcII-R. Consistent with the uptake results, FcII-R activation with its specific ligand caused a similar generation of reactive oxygen species and TNF- release as observed after treatment with DQ12. In conclusion, our results indicate a major role of FcII-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.

GTPases; particles; phagocytosis; reactive oxygen species