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Cell Mol Life Sci. 2011 Dec;68(23):3933-47. doi: 10.1007/s00018-011-0688-4. Epub 2011 May 2.

Impaired Rho GTPase activation abrogates cell polarization and migration in macrophages with defective lipolysis.

Author information

1
Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Austria.

Erratum in

  • Cell Mol Life Sci. 2013 Jul;70(14):2621.

Abstract

Infiltration of monocytes and macrophages into the site of inflammation is critical in the progression of inflammatory diseases such as atherosclerosis. Cell migration is dependent on the continuous organization of the actin cytoskeleton, which is regulated by members of the small Rho GTPase family (RhoA, Cdc42, Rac) that are also important for the regulation of signal transduction pathways. We have recently reported on reduced plaque formation in an atherosclerotic mouse model transplanted with bone marrow from adipose triglyceride lipase-deficient (Atgl-/-) mice. Here we provide evidence that defective lipolysis in macrophages lacking ATGL, the major enzyme responsible for triacylglycerol hydrolysis, favors an anti-inflammatory M2-like macrophage phenotype. Our data implicate an as yet unrecognized principle that insufficient lipolysis influences macrophage polarization and actin polymerization, resulting in impaired macrophage migration. Sustained phosphorylation of focal adhesion kinase [due to inactivation of its phosphatase by elevated levels of reactive oxygen species (ROS)] results in defective Cdc42, Rac1 and RhoA activation and in increased and sustained activation of Rac2. Inhibition of ROS production restores the migratory capacity of Atgl-/- macrophages. Since monocyte and macrophage migration are a prerequisite for infiltrating the arterial wall, our results provide a molecular link between lipolysis and the development of atherosclerosis.

PMID:
21533980
PMCID:
PMC3214256
DOI:
10.1007/s00018-011-0688-4
[Indexed for MEDLINE]
Free PMC Article

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