Critical role of MARCO in crystalline silica-induced pulmonary inflammation.

Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Center for Environmental Health Sciences, Missoula, MT 59812, USA.
Toxicological Sciences (Impact Factor: 4.48). 02/2009; 108(2):462-71. DOI: 10.1093/toxsci/kfp011
Source: PubMed

ABSTRACT Chronic exposure to crystalline silica can lead to the development of silicosis, an irreversible, inflammatory and fibrotic pulmonary disease. Although, previous studies established the macrophage receptor with collagenous structure (MARCO) as an important receptor for binding and uptake of crystalline silica particles in vitro, the role of MARCO in regulating the inflammatory response following silica exposure in vivo remains unknown. Therefore, we determined the role of MARCO in crystalline silica-induced pulmonary pathology using C57Bl/6 wild-type (WT) and MARCO(-/-) mice. Increased numbers of MARCO(+) pulmonary macrophages were observed following crystalline silica, but not phosphate-buffered saline and titanium dioxide (TiO(2)), instillation in WT mice, highlighting a specific role of MARCO in silica-induced pathology. We hypothesized that MARCO(-/-) mice will exhibit diminished clearance of silica leading to enhanced pulmonary inflammation and exacerbation of silicosis. Alveolar macrophages isolated from crystalline silica-exposed mice showed diminished particle uptake in vivo as compared with WT mice, indicating abnormalities in clearance mechanisms. Furthermore, MARCO(-/-) mice exposed to crystalline silica showed enhanced acute inflammation and lung injury marked by increases in early response cytokines and inflammatory cells compared with WT mice. Similarly, histological examination of MARCO(-/-) lungs at 3 months post-crystalline silica exposure showed increased chronic inflammation compared with WT; however, only a small difference was observed with respect to development of fibrosis as measured by hydroxyproline content. Altogether, these results demonstrate that MARCO is important for clearance of crystalline silica in vivo and that the absence of MARCO results in exacerbations in innate pulmonary immune responses.


Available from: Celine A Beamer, Jun 01, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: MARCO is the predominant scavenger receptor for recognition and binding of silica particles by alveolar macrophages (AM). Previously, it was shown that mice null for MARCO have a greater inflammatory response to silica, but the mechanism was not described. The aim of this study was to determine the relationship between MARCO and NLRP3 inflammasome activity. Silica increased NLRP3 inflammasome activation and release of the proinflammatory cytokine, IL-1β, to a greater extent in MARCO(-/-) AM compared to wild type (WT) AM. Furthermore, in MARCO(-/-) AM there was greater cathepsin B release from phagolysosomes, Caspase-1 activation, and acid sphingomyelinase activity compared to WT AM, supporting the critical role played by lysosomal membrane permeabilization (LMP) in triggering silica-induced inflammation. The difference in sensitivity to LMP appears to be in cholesterol recycling since increasing cholesterol in AM by treatment with U18666A decreased silica-induced NLRP3 inflammasome activation, and cells lacking MARCO were less able to sequester cholesterol following silica treatment. Taken together, these results demonstrate that MARCO contributes to normal cholesterol uptake in macrophages; therefore, in the absence of MARCO, macrophages are more susceptible to a greater inflammatory response by particulates known to cause NLRP3 inflammasome activation and the effect is due to increased LMP.
    Research Journal of Immunology 06/2014; 2014:304180. DOI:10.1155/2014/304180
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We hypothesized that infusion of bone marrow mononuclear cells (BMMCs) in the late stages of silica-induced damage would reduce the remodelling process in a murine model of silicosis. C57BL/6 mice were assigned to 2 groups. In the SIL group, mice were instilled with a silica particle suspension intratracheally. Control (C) mice received saline under the same protocol. On the 40th day, some of the animals from both groups were killed. The others were treated with either saline or BMMCs (1×106cells) intravenously (C+BMMC and SIL+BMMC), and the mice were killed 70 days after the start of the protocol. In the mice in the SIL+BMMC group, collagen deposition, the presence of silica particles inside nodules, the presence of macrophages and cells reactive for inducible nitric oxide synthase were reduced. Lung parameters also improved. Beyond that, the total and differential cellularity of bronchoalveolar lavage fluid, immunoexpression of transforming growth factor-β, the number of T regulatory cells and apoptosis were increased. However, the presence of male donor cells in lung tissue was not observed using GFP+ cells (40d) or Y chromosome DNA (70d). Therefore, BMMC therapy in the late stages of experimental silicosis improved lung function by diminishing fibrosis but inflammatory cells persisted, which could be related to expansion of T regulatory cells, responsible for the beneficial effects of cell therapy.
    PLoS ONE 10/2014; 9(10):e109982. DOI:10.1371/journal.pone.0109982 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Silica inhalation leads to the development of the chronic lung disease, silicosis. Macrophages are killed by uptake of non-opsonized silica particles and this is believed to play a critical role in the etiology of silicosis. However, the mechanism of non-opsonized particle uptake is not well understood. We have compared the molecular events associated with non-opsonized and opsonized particle phagocytosis. Both Rac and RhoA GTPases are activated upon non-opsonized 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 endo-lysosome-to-phagosome fusion do not significantly differ between the pathways. Inhibitors of tyrosine kinases, actin polymerization, and the phosphatidylinositol cascade prevent opsonized and non-opsonized particle uptake similarly. Inhibition of silica particle uptake prevents silica-induced cell death. Microtubule depolymerization abolished uptake of complement-opsonized and non-opsonized particles, but not Ab-opsonized particles. Interestingly, regrowth of microtubules allowed uptake of new non-opsonized particles but not ones bound to cells in the absence of microtubules. While complement-mediated uptake requires macrophages to be PMA-primed, untreated cells phagocytose non-opsonized silica and latex. Thus, it appears that non-opsonized particle uptake is accomplished by a pathway with unique characteristics. © 2014 by The American Society for Cell Biology.
    Molecular Biology of the Cell 11/2014; 26(3). DOI:10.1091/mbc.E14-08-1301 · 4.55 Impact Factor