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Arginase I Induction by Modified Lipoproteins in Macrophages: A Peroxisome Proliferator-Activated Receptor-/-Mediated Effect that Links Lipid Metabolism and Immunity

Departamento de Bioquímica y Biología Molecular y Genética (A.G.-S., M.L.C., I.C.), and Unidad de Parasitología (C.G.-N.), Facultad de Veterinaria, Universidad de Extremadura, 10071 Cáceres, Spain; Howard Hughes Medical Institute (P.T., C.M.), Molecular Biology Institute, and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California 90095; and Departamento de Bioquímica y Biología Molecular (A.C.), Universidad de Las Palmas de Gran Canaria, Las Palmas 35016, Spain

Address all correspondence and requests for reprints to: Ines Corraliza, Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Veterinaria, Universidad de Extremadura. Avenida de la Universidad s/n, 10071 Cáceres, Spain. E-mail: corragen{at}unex.es.

Macrophages are phagocytic cells that play essential roles in innate immunity and lipid homeostasis. The uptake of modified lipoproteins is an important early event in the development of atherosclerosis. We analyzed the ability of modified low-density lipoprotein (LDL) (oxidized and acetylated) to alter the expression and activity of arginases (ArgI and ArgII) in macrophages. We show that ArgI expression is potently induced by both oxidized and acetylated LDL in macrophages. We further show that this effect is mediated by peroxisome proliferator-activated receptors (PPAR). ArgI expression is highly responsive to agonists for PPAR and PPAR but not PPAR. Moreover, the induction of ArgI by both PPAR agonists and IL-4 is blocked in macrophages from PPAR- and PPAR-deficient mice. Functionally, PPAR activity induces macrophage activation toward a more Th2 immune phenotype in a model of Leishmania major infection. We show that PPAR and - ligands promote intracellular amastigote growth in infected macrophages, and this effect is dependent on both PPAR expression and Arg activity. Collectively, our results strongly suggest that ArgI is a key marker of the alternative program triggered by PPAR in macrophages.

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