Adipose triglyceride lipase acts on neutrophil lipid droplets to regulate substrate availability for lipid mediator synthesis

Journal of Leukocyte Biology

Dagmar Kolb¹  Katharina Jandl¹  Juliane Dorow¹  Dagmar Kratky¹  Madeleine Goeritzer¹  Erin E. Kershaw¹  Heimo Strohmaier¹  Stefanie Schlager¹  Albert Wölfler#¹  Robert Frei¹  Achim Lass–¹  Thomas O. Eichmann–¹  Uta Ceglarek¹  Akos Heinemann  and¹  Angelika Rosenberger#¹  Nemanja Vujic¹  Andrea Dichlberger ¹ 

[1] Institutes of Molecular Biology and Biochemistry and  Experimental and Clinical Pharmacology, Center for Medical Research, and #Division of Hematology, Medical University of Graz, Graz, Austria; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; LIFE“Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; –Institute of Molecular Biosciences, University of Graz, Graz, Austria; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and   Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland

关键词: inflammatory cells;    arachidonic acid;    eicosanoids;    lipolysis;   

DOI  :  10.1189/jlb.3A0515-206R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

In humans, mutations in ATGL lead to TG accumulation in LDs of most tissues and cells, including peripheral blood leukocytes. This pathologic condition is called Jordans’ anomaly, in which functional consequences have not been investigated. In the present study, we tested the hypothesis that ATGL plays a role in leukocyte LD metabolism and immune cell function. Similar to humans with loss-of-function mutations in ATGL, we found that global and myeloid-specific Atgl−/− mice exhibit Jordans’ anomaly with increased abundance of intracellular TG-rich LDs in neutrophil granulocytes. In a model of inflammatory peritonitis, lipid accumulation was also observed in monocytes and macrophages but not in eosinophils or lymphocytes. Neutrophils from Atgl−/− mice showed enhanced immune responses in vitro, which were more prominent in cells from global compared with myeloid-specific Atgl−/− mice. Mechanistically, ATGL−/− as well as pharmacological inhibition of ATGL led to an impaired release of lipid mediators from neutrophils. These findings demonstrate that the release of lipid mediators is dependent on the liberation of precursor molecules from the TG-rich pool of LDs by ATGL. Our data provide mechanistic insights into Jordans’ anomaly in neutrophils and suggest that ATGL is a potent regulator of immune cell function and inflammatory diseases.

【 授权许可】

Unknown