ToxSci Advance Access originally published online on October 4, 2008
Toxicological Sciences 2009 107(1):238-246; doi:10.1093/toxsci/kfn210
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Differential Binding of Inorganic Particles to MARCO
* Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812
Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden
1 To whom correspondence should be addressed at Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, 280B Skaggs Building, 32 Campus Drive, University of Montana, Missoula, MT 59812. Fax: 406-243-2807. E-mail: andrij.holian{at}umontana.edu.
Received July 22, 2008; accepted September 26, 2008
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Abstract |
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Alveolar macrophages (AM) in the lung have been documented to play pivotal roles in inflammation and fibrosis (silicosis) following inhalation of crystalline silica (CSiO2). In contrast, exposure to either titanium dioxide (TiO2) or amorphous silica (ASiO2) 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 TiO2. Only CSiO2 is toxic to AM, while ASiO2 and TiO2 are not. We hypothesize that differences in induction of pathology between toxic CSiO2 and nontoxic particles ASiO2 and TiO2 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 (ASiO2, CSiO2, and TiO2) 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 TiO2 required divalent cations (viz., Ca+2 and/or Mg+2) for binding to MARCO, and results from competitive binding studies supported the notion that TiO2 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.
Key Words: MARCO; crystalline silica; amorphous silica; TiO2; binding; apoptosis.
Disclaimer: The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of National Center for Research Resources, National Institute of Environmental Health Sciences, or National Institutes of Health.
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