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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.

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    • "Previous in vivo results showed an increased inflammatory response in MARCO −/− mice compared with WT mice following 24 hrs of silica exposure [14]. There was an increase in total protein levels and total number of lavage cells and a significant increase in infiltration of immune cells such as AM, DC, and neutrophils in MARCO −/− mice compared with WT mice, all indicating an increase in inflammation in "
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    • "Furthermore, recent findings regarding the NOD-like receptor family, pryin domain containing 3 (NLRP3, Nalp3)-inflammasome, have contributed substantially to our understanding of the sequential cellular events occurring when silica is inhaled into the pulmonary region and alveolar macrophages try to treat silica particles as a foreign substance (Cassel, 2008; Dostert, 2008; Hormung, 2008). At first, initial recognition of silica occurs by cell membrane receptors such as the macrophage receptor with collagenous structure (MARCO), scavenger receptor (SR)-AI and SR-AII (Brown, 2007; Hamilton, 2006; Thakur, 2009). The next stage involves capture of silica by macrophages and entrapment within lysosomes and their activation of the nucleotidebinding domain and leucine-rich repeat containing proteins, the NLRP3 inflammasome, to cleave pro-caspase 1 to an active form (Cassel, 2008; Dostert, 2008; Hormung, 2008). "
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