Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Aflaki, E.
Role of adipose triglyceride lipase in macrophage inflammation, cytoskeleton rearrangement and cell survival
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2011. pp.102.
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- Autor*innen der Med Uni Graz:
- Aflaki Elma
- Betreuer*innen:
- Birner-Grünberger Ruth
- Heinemann Akos
- Kratky Dagmar
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- 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. Here we provide evidence that defective lipolysis in macrophages lacking adipose triglyceride lipase (ATGL), the major enzyme responsible for triacylglycerol (TG) hydrolysis, favors an anti-inflammatory M2 macrophage phenotype. Our data implicate 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 increased and sustained activation of Rac2. Inactivation of Rac1 and Cdc42 lead to defective polarization and directional movement toward the chemoattractants. Furthermore, RhoA inactivation may cause impaired migration and actin polymerization in the presence of chemoattractant. Inhibition of ROS production leads to focal adhesion kinase (FAK) activation transiently and restores the migratory capacity of Atgl-/- macrophages. Macrophage apoptosis has an important implication in definition of early and late atherosclerosis. We found reduced plaque formation in model low density lipoprotein receptor (Ldlr-/-) transplanted with bone marrow from Atgl-/- mice. To elucidate the reason of less plaque formation, programmed cell death was investigated in primary peritoneal Atgl-/- macrophages. We observed elevated levels of cytosolic Ca2+ and ROS, stimulated cytochrome c release and nuclear localization of apoptosis inducing factor (AIF). Fragmented mitochondria prior to cell death were indicative of the mitochondrial apoptosis pathway being triggered as a consequence of defective lipolysis. Other typical markers of apoptosis, such as externalization of phosphatidylserine in the plasma membrane, caspase 3 and poly (ADP-ribose) polymerase cleavage, were increased in Atgl-/- macrophages. In addition, Ca2+ depletion from ER triggers activation of ATF4/CHOP pathway that defines ER stress induction in Atgl-/- macrophages. An artificial increase of cellular TG levels by incubating wild-type macrophages with very low-density lipoprotein almost completely mimicked the apoptotic phenotype observed in Atgl-/- macrophages. Results obtained during the present study define a novel pathway linking intracellular TG accumulation to mitochondrial dysfunction and ER stress leading to programmed cell death in macrophages.