title: Macrophages phagocytose nonopsonized silica particles using a unique microtubule-dependent pathway.
abstract: Silica inhalation leads to the development of the chronic lung disease silicosis. Macrophages are killed by uptake of nonopsonized silica particles, and this is believed to play a critical role in the etiology of silicosis. However, the mechanism of nonopsonized-particle uptake is not well understood. We compared the molecular events associated with nonopsonized- and opsonized-particle phagocytosis. Both Rac and RhoA GTPases are activated upon nonopsonized-particle exposure, whereas opsonized particles activate either Rac or RhoA. All types of particles quickly generate a PI(3,4,5)P3 and F-actin response at the particle attachment site. After formation of a phagosome, the events related to endolysosome-to-phagosome fusion do not significantly differ between the pathways. Inhibitors of tyrosine kinases, actin polymerization, and the phosphatidylinositol cascade prevent opsonized- and nonopsonized-particle uptake similarly. Inhibition of silica particle uptake prevents silica-induced cell death. Microtubule depolymerization abolished uptake of complement-opsonized and nonopsonized particles but not Ab-opsonized particles. Of interest, regrowth of microtubules allowed uptake of new nonopsonized particles but not ones bound to cells in the absence of microtubules. Although complement-mediated uptake requires macrophages to be PMA-primed, untreated cells phagocytose nonopsonized silica and latex. Thus it appears that nonopsonized-particle uptake is accomplished by a pathway with unique characteristics.
authors.affiliation: Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269.
authors.forename: Renée M
authors.initials: RM
authors.lastname: Gilberti
authors.affiliation: Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269 david.knecht@uconn.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Knecht
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D016923:Cell Death; D004789:Enzyme Activation; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis; D012822:Silicon Dioxide / Q000378:metabolism / Q000633:toxicity*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D000199:Actins; D009479:Neuropeptides; D018129:Phosphatidylinositol Phosphates; C484602:Rac1 protein, mouse; D012822:Silicon Dioxide; C526380:RhoA protein, mouse; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein