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.