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MARCO modulates asbestos‐induced Rac1 mitochondrial import and H2O2 production
Author(s) -
Murthy Shubha,
Kobzik Lester,
Carter A Brent
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.769.2
Subject(s) - rac1 , mitochondrion , microbiology and biotechnology , asbestos , asbestosis , chemistry , macrophage , biology , biochemistry , signal transduction , materials science , in vitro , metallurgy
Rac1 is a second messenger involved in many cellular processes, including the production of H 2 O 2 . Our previous observations demonstrate that macrophage Rac1 activation is crucial for the development of pulmonary fibrosis, and Rac1 localizes to the mitochondria in asbestosis patients. Asbestos induced Rac1 translocation to the mitochondria and mediated H 2 O 2 production. The mechanism by which asbestos activates Rac1 is not known. The macrophage receptor with collagenous structure (MARCO) has been shown to provide innate immune defense against inhaled particles and pathogens. We, therefore, hypothesized that MARCO binds asbestos and modulates Rac1 import into the mitochondria and mitochondrial H 2 O 2 production. Both the total and cell surface expression of MARCO was greater in macrophages from asbestosis patients compared to normal subjects. To address if MARCO modulated Rac1 import, we silenced MARCO and found that it resulted in reduced Rac1 mitochondrial localization. Furthermore, inhibition of ligand binding of MARCO dramatically decreased chrysotile‐induced mitochondrial H 2 O 2 . These results suggest that MARCO binds asbestos and, together with Rac1, is involved in upstream signaling events leading to asbestos‐induced mitochondrial H 2 O 2 production. This work was supported by NIH grants ES015981 and ES014871 and Merit Review from Department of Veterans Affairs.