We of scavenger receptor a family in lung inflammation from exposure to environmental particles
ABSTRACT Both immune and non-immune cells express an extensive array of scavenger receptors that bind a variety of ligands including bacterial cell-wall components and lipoproteins. Over the past several years, significant advances have been made in elucidating the role of scavenger receptors, predominantly Class A scavenger receptors SR-A I/II and MARCO, on macrophages in the binding of environmental particles such as crystalline silica and titanium dioxide. Recent evidence indicates that the binding of crystalline silica to scavenger receptors leads to apoptosis of macrophages and release of mediators (e.g., proinflammatory cytokines) contributing to lung inflammation and fibrosis. In this review, we examine the evidence for the role of SR-A I/II and MARCO in binding of the environmental particles and signaling initiated by particle-receptor interaction. Emerging concepts on the molecular details of signaling cascades by engagement of scavenger receptors by the environmental particles are also discussed.
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ABSTRACT: We have demonstrated previously that the acid-treated multi-walled carbon nanotubes (aci-MWCNTs) and taurine functionalized MWCNTs (tau-MWCNTs) induced differential pulmonary toxicity in mice after instillation exposure. In order to compare differences of cytotoxicity between the aci- and tau-MWCNTs, RAW 264.7 cells (a murine macrophage cell line) were chosen to be exposed to the aci- and tau-MWCNTs at concentrations of 0, 5, 20, 40, and 80μg/ml for 12 or 24h respectively. The results showed that although the aci- and tau-MWCNTs induced only mild decrease in cell viability to RAW 264.7 cells, the two types of MWCNTs elicited significant increase in apoptosis and decreased ability in cellular phagocytosis. Moreover, by using the specific inhibitors, we found that the scavenger receptors (SR) and caspase-9 were actively involved in the apoptosis induced by the aci- and tau-MWCNTs. The taurine functionalized MWCNTs (tau-MWCNTs) showed less cytotoxicity and apoptotic effect to RAW 264.7 cells than those of aci-MWCNTs. Taken together, the results indicated the important role of scavenger receptors and mitochondria in the apoptosis induced by MWCNTs.Toxicology in Vitro 06/2012; 26(6):799-806. DOI:10.1016/j.tiv.2012.05.010 · 3.21 Impact Factor
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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.Toxicological Sciences 02/2009; 108(2):462-71. DOI:10.1093/toxsci/kfp011 · 4.48 Impact Factor
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ABSTRACT: Alveolar macrophages (AM) in the lung have been documented to play pivotal roles in inflammation and fibrosis (silicosis) following inhalation of crystalline silica (CSiO(2)). In contrast, exposure to either titanium dioxide (TiO(2)) or amorphous silica (ASiO(2)) is considered relatively benign. The scavenger receptor macrophage receptor with collagenous structure (MARCO), expressed on AM, binds and internalizes environmental particles such as silica and TiO(2). Only CSiO(2) is toxic to AM, while ASiO(2) and TiO(2) are not. We hypothesize that differences in induction of pathology between toxic CSiO(2) and nontoxic particles ASiO(2) and TiO(2) may be related to their differential binding to MARCO. In vitro studies with Chinese hamster ovary (CHO) cells transfected with human MARCO and mutants were conducted to better characterize MARCO-particulate (ASiO(2), CSiO(2), and TiO(2)) interactions. Results with MARCO-transfected CHO cells and MARCO-specific antibody demonstrated that the scavenger receptor cysteine-rich (SRCR) domain of MARCO was required for particle binding for all the tested particles. Only TiO(2) required divalent cations (viz., Ca(+2) and/or Mg(+2)) for binding to MARCO, and results from competitive binding studies supported the notion that TiO(2) and both the silica particles bound to different motifs in SRCR domain of MARCO. The results also suggest that particle shape and/or crystal structure may be the determinants linking particle binding to MARCO and cytotoxicity. Taken together, these results demonstrate that the SRCR domain of MARCO is required for particle binding and that involvement of different regions of SRCR domain may distinguish downstream events following particle binding.Toxicological Sciences 11/2008; 107(1):238-46. DOI:10.1093/toxsci/kfn210 · 4.48 Impact Factor