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: 3.85). 02/2009; 108(2):462-71. DOI: 10.1093/toxsci/kfp011
Source: PubMed


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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Available from: Celine A Beamer, Oct 08, 2015
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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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    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
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    • "Death of alveolar macrophages by silica might further promote inflammation and autoimmunity by impairing the clearance of silica and apoptotic cells, and by generating apoptotic material. In support of this, deficiency of either scavenger receptors macrophage receptor with a collagenous structure (MARCO) or CD204, expressed mainly on macrophages, was shown to impair silica clearance and exacerbate silica-induced lung inflammation [154,155]. Additionally, MARCO-deficient mice are defective in clearing apoptotic cells [156] and both MARCO and CD204 have been argued to promote tolerance to apoptotic cell material [157]. These observations suggest that scavenger receptor-mediated uptake of silica and subsequent macrophage cell death may adversely affect clearance of dead and dying cells, which, in turn, could impact self-tolerance [158,159] and promote autoimmunity. "
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    ABSTRACT: There is substantial evidence that environmental triggers in combination with genetic and stochastic factors play an important role in spontaneous autoimmune disease. Although the specific environmental agents and how they promote autoimmunity remain largely unknown, in part because of diverse etiologies, environmentally induced autoimmune models can provide insights into potential mechanisms. Studies of idiopathic and environmentally induced systemic autoimmunity show that they are mediated by common adaptive immune response genes. By contrast, although the innate immune system is indispensable for autoimmunity, there are clear differences in the molecular and cellular innate components that mediate specific systemic autoimmune diseases, suggesting distinct autoimmune-promoting pathways. Some of these differences may be related to the bifurcation of toll-like receptor signaling that distinguishes interferon regulatory factor 7-mediated type I interferon production from nuclear factor-κB-driven proinflammatory cytokine expression. Accordingly, idiopathic and pristane-induced systemic autoimmunity require both type I interferon and proinflammatory cytokines whereas the less aggressive mercury-induced autoimmunity, although dependent on nucleic acid-binding toll-like receptors, does not require type I interferon but needs proinflammatory cytokines. Scavenger receptors and the inflammasome may contribute to silica-induced autoimmunity. Greater understanding of the innate mechanisms responsible for idiopathic and environmentally induced autoimmunity should yield new information into the processes that instigate and drive systemic autoimmunity.
    BMC Medicine 04/2013; 11(1):100. DOI:10.1186/1741-7015-11-100 · 7.25 Impact Factor
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    • "AhR REGULATES SILICA-INDUCED INFLAMMATION assessment of tissue sections from SiO 2 -exposed lung was performed. For these studies, 6-to 8-week-old C57Bl/6 and AhR À/À mice were exposed to 1 mg SiO 2 or vehicle once a week for 4 weeks and inflammation assessed at 1 month as described in Supplementary figure 1. Lung wet weight was higher in SiO 2 -exposed C57Bl/6 (1.59-fold) and AhR À/À mice (1.42-fold) compared with their respective vehicle-exposed mice indicating the presence of either edema or infiltration of inflammatory cells (Table 1) (Thakur et al., 2009). Representative tissue sections from vehicle-exposed C57Bl/6 and AhR À/À mice showed normal tissue architecture, indicating that the absence of the AhR does not lead to gross anatomical changes in the lungs (data not shown). "
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    ABSTRACT: The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is responsible for mediating a variety of pharmacological and toxicological effects caused by halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, recent evidence has revealed that the AhR also has numerous physiological roles aside from xenobiotic metabolism, including regulation of immune and inflammatory signaling as well as normal development and homeostasis of several organs. To investigate the role of the AhR in crystalline silica (SiO(2))-induced inflammation and fibrosis, C57Bl/6 and AhR(-/)(-) mice were exposed to SiO(2) or vehicle. Similarly, C57Bl/6 mice were exposed to SiO(2) and TCDD either simultaneously or sequentially to assess whether AhR activation alters inflammation and fibrosis. SiO(2)-induced acute lung inflammation was more severe in AhR(-)(/-) mice; however, the fibrotic response of AhR(-)(/-) mice was attenuated compared with C57Bl/6 mice. In a model of chronic SiO(2) exposure, AhR activation by TCDD in C57Bl/6 mice resulted in reduced inflammation; however, the fibrotic response was not affected. Bone marrow-derived macrophages (BMM) from AhR(-)(/-) mice also produced higher levels of cytokines and chemokines in response to SiO(2). Analysis of gene expression revealed that BMM derived from AhR(-)(/-) mice exhibit increased levels of pro-interleukin (IL)-1β, IL-6, and Bcl-2, yet decreased levels of signal transducers and activators of transcription (STAT)2, STAT5a, and serpin B2 (Pai-2) in response to SiO(2).
    Toxicological Sciences 01/2012; 126(2):554-68. DOI:10.1093/toxsci/kfs024 · 3.85 Impact Factor
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