Silica-Directed Mast Cell Activation Is Enhanced by Scavenger Receptors

Abstract

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.CgKit 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 Fc⑀RI-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 Fc⑀RI 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. Keywords: B6.Cg-kitW-sh sash mouse; CD204; macrophage receptor with collagenous structure; mast cell; silicosis; SR-A Among environmental exposures that lead to pathologic changes in tissues is crystalline silica, which can result in occupational silicosis from inhalation of silica dusts in manufacturing, construction, farming, and mining operations. Silicosis, for which there is no effective treatment, leads to decreased pulmonary function and increased susceptibility to diseases of the respiratory tract (1, 2).Involvement of mast cells in silica-induced pulmonary inflammation has been suggested by two clinical observations. First, the number of mast cells within the lungs of individuals exposed to silica dust is increased (3). Second, an increase in mast cells staining for basic fibroblast growth factor located within silicotic nodules has been reported in lung sections obtained from patients with silicosis (4). Despite the suggestive CLINICAL RELEVANCEThis 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.evidence for a role of mast cells in the development of silicosis, there are ...

Mast Cells Contribute to Bleomycin-Induced Lung Inflammation and Injury in Mice through a Chymase/Mast Cell Protease 4–Dependent Mechanism

“…Indeed, such potential anti-inflammatory or immunosuppressive effects of MCs have already been observed in mouse models of skin graft tolerance (42)(43)(44), contact hypersensitivity to UV-B irradiation or haptens (45,46), and chronic allergic dermatitis (47). Such a biphasic effect of MCs could also contribute to the heterogeneity in reports of the role of MCs in BLM-induced lung inflammation (28)(29)(30)(31)(32). However, we found no difference in levels of inflammation in BALF and lung between Kit +/+ and MC-deficient Kit W-sh/W-sh mice 28 d after BLM treatment, a time point when the inflammation level was highly reduced in both groups as compared with days 7 and 14.…”

Concurrent Inhibition of Kit- and FcϵRI-Mediated Signaling: Coordinated Suppression of Mast Cell Activation

“…Wells used for total cells were not washed. Cells were lysed with 0.1% Triton X-100, and 100 l of the lysate was then transferred to a 96-well plate for ␤-hexosaminidase determination (Brown et al, 2007). The percent adherent cells were calculated as [(absorbance of sample Ϫ background)/(absorbance of total cell lysates Ϫ background)] ϫ 100%.…”

“…Degranulation was monitored by ␤-hexosaminidase release (Brown et al, 2007) performed in a U-bottom 96-well plate (100-l final volume). IgE-sensitized HuMCs (7 ϫ 10 3 cells per well) or BMMCs (2.5 ϫ 10 5 cells per well) were preincubated with inhibitors (0.001-10 M) for 15 min before the addition of the stimuli.…”

The mast cell and allergic diseases: role in pathogenesis and implications for therapy

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