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Target Concepts:
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Query: UMLS:C0037116 (
silicosis
)
1,822
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Alveolar macrophages express the class A scavenger receptor (
CD204
) (Babaev VR, Gleaves LA, Carter KJ, Suzuki H, Kodama T, Fazio S, and Linton MF. Arterioscler Thromb Vasc Biol 20: 2593-2599, 2000); yet its role in vivo in lung defense against environmental particles has not been clearly defined. In the current study,
CD204
null mice (129Sv background) were used to investigate the link between
CD204
and downstream events of inflammation and fibrosis following silica exposure in vivo.
CD204
-/- macrophages were shown to recognize and uptake silica in vitro, although this response was attenuated compared with 129Sv wild-type mice. The production of tumor necrosis factor-alpha in lavage fluid was significantly enhanced in
CD204
null mice compared with wild-type mice following silica exposure. Moreover, after exposure to environmental particles,
CD204
-/- macrophages exhibited improved cell viability in a dose-dependent manner compared with wild-type macrophages. Finally, histopathology from a murine model of chronic
silicosis
in 129Sv wild-type mice displayed typical focal lesions, interstitial thickening with increased connective tissue matrix, and cellular infiltrate into air space. In contrast,
CD204
-/- mice exhibited little to no deposition of collagen, yet they demonstrated enhanced accumulation of inflammatory cells largely composed of neutrophils. Our findings point to an important role of
CD204
in mounting an efficient and appropriately regulated immune response against inhaled particles. Furthermore, these results indicate that the functions of
CD204
are critical to the development of fibrosis and the resolution of inflammation.
...
PMID:Scavenger receptor class A type I/II (CD204) null mice fail to develop fibrosis following silica exposure. 1584 12
Inhalation of crystalline silica (SiO
2
) is a risk factor of systemic autoimmune diseases such as systemic sclerosis (SSc) and fibrotic pulmonary disorders such as
silicosis
. A defect of apoptotic cell clearance (i.e., efferocytosis, a key process in the resolution of inflammation) is reported in macrophages from patients with fibrotic or autoimmune diseases. However, the precise links between SiO
2
exposure and efferocytosis impairment remain to be determined. Answering to this question may help to better link innate immunity and fibrosis. In this study, we first aim to determine whether SiO
2
might alter efferocytosis capacities of human and mouse macrophages. We secondly explore possible mechanisms explaining efferocytosis impairment, with a specific focus on macrophage polarization and on the RhoA/ROCK pathway, a key regulator of cytoskeleton remodeling and phagocytosis. Human monocyte-derived macrophages (MDM) and C57BL/6J mice exposed to SiO
2
and to CFSE-positive apoptotic Jurkat cells were analyzed by flow cytometry to determine their efferocytosis index (EI). The effects of ROCK inhibitors (Y27632 and Fasudil) on EI of SiO
2
-exposed MDM and MDM from SSc patients were evaluated
in vitro
. Our results demonstrated that SiO
2
significantly decreased EI of human MDM
in vitro
and mouse alveolar macrophages
in vivo
. In human MDM, this SiO
2
-associated impairment of efferocytosis, required the expression of the membrane receptor SR-B1 and was associated with a decreased expression of M2 polarization markers (CD206,
CD204
, and CD163). F-actin staining, RhoA activation and impairment of efferocytosis, all induced by SiO
2
, were reversed by ROCK inhibitors. Moreover, the EI of MDM from SSc patients was similar to the EI of
in vitro
- SiO
2
-exposed MDM and Y27632 significantly increased SSc MDM efferocytosis capacities, suggesting a likewise activation of the RhoA/ROCK pathway in SSc. Altogether, our results demonstrate that SiO
2
exposure may contribute to the impairment of efferocytosis capacities of mouse and human macrophages but also of MDM in SiO
2
-associated autoimmune diseases and fibrotic disorders such as SSc; in this context, the silica/RhoA/ROCK pathway may constitute a relevant therapeutic target.
...
PMID:Crystalline Silica Impairs Efferocytosis Abilities of Human and Mouse Macrophages: Implication for Silica-Associated Systemic Sclerosis. 3213 4
