Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 26, Issue 3, Pages 518-529Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E14-08-1301
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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.
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