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ToxSci Advance Access published online on October 4, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn210
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Differential binding of inorganic particles to MARCO

Sheetal A. Thakur*, Raymond Hamilton, Jr.*, Timo Pikkarainen{dagger} and Andrij Holian*

* University of Montana, Department of Biomedical and Pharmaceutical Sciences, Center for Environmental Health Sciences, 32 Campus Dr., SB 280B, Missoula MT 59812 {dagger} Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden

Address correspondence to: Andrij Holian, Ph.D., Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, 280B Skaggs Building, 32 Campus Drive, University of Montana, E-mail: andrij.holian{at}umontana.edu, T: 406-243-4018, Fax: 406-243-2807

Received July 22, 2008; revision received September 24, 2008; accepted September 26, 2008


  Abstract

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 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 non-toxic particles ASiO2 and TiO2 may be related to their differential binding to MARCO. In vitro studies with 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 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.

Email addresses of authors: sheetal.thakur{at}umontana.edu, raymond.hamilton{at}umontana.edu, Timo.Pikkarainen{at}ki.se, andrij.holian{at}umontana.edu


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S. A. Thakur, C. A. Beamer, C. T. Migliaccio, and A. Holian
Critical Role of MARCO in Crystalline Silica-Induced Pulmonary Inflammation
Toxicol. Sci., April 1, 2009; 108(2): 462 - 471.
[Abstract] [Full Text] [PDF]


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