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Silica-Directed Mast Cell Activation Is Enhanced by Scavenger Receptors

Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; and Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana

Correspondence and requests for reprints should be addressed to Jared M. Brown, Ph.D., Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11C209, 10 Center Drive, MSC 1881, Bethesda, MD 20892–1881. E-mail: jmbrown{at}niaid.nih.gov

Inhalation of crystalline silica results in pulmonary fibrosis and silicosis. It has been suggested that mast cells play a role in these conditions. How mast cells would influence pathology is unknown. We thus explored mast cell interactions with silica in vitro and in B6.Cg-kit^W-sh mast cell–deficient mice. B6.Cg-kit^W-sh mice did not develop inflammation or significant collagen deposition after instillation of silica, while C57Bl/6 wild-type mice did have these findings. Given this supporting evidence of a role for mast cells in the development of silicosis, we examined the ability of silica to activate mouse bone marrow–derived mast cells (BMMC), including degranulation (-hexosaminidase release); production of reactive oxygen species (ROS) and inflammatory mediators; and the effects of silica on FcRI-dependent activation. Silica did not induce mast cell degranulation. However, TNF-, IL-13, monocyte chemotactic protein-1, protease activity, and production of ROS were dose-dependently increased after silica exposure, and production was enhanced after FcRI stimulation. This mast cell activation was inhibited by anti-inflammatory compounds. As silica mediates some effects in macrophages through scavenger receptors (SRs), we first determined that mast cells express scavenger receptors; then explored the involvement of SR-A and macrophage receptor with colleagenous structure (MARCO). Silica-induced ROS formation, apoptosis, and TNF- production were reduced in BMMC obtained from SR-A, MARCO, and SR-A/MARCO knockout mice. These findings demonstrate that silica directs mast cell production of inflammatory mediators, in part through SRs, providing insight into critical events in the pathogenesis and potential therapeutic targets in silicosis.

Key Words: B6.Cg-kit^W-sh sash mouse • CD204 • macrophage receptor with collagenous structure • mast cell • silicosis • SR-A

CLINICAL RELEVANCE This study demonstrates a role for mast cells in silicosis and is the first study to examine direct effects of silica on mast cell biology. It provides evidence that treatment of silicosis should explore mast cells as a potential therapeutic target.

 

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