title: Human macrophage differentiation induces OCTN2-mediated L-carnitine transport through stimulation of mTOR-STAT3 axis.
abstract: l-Carnitine, in addition to playing a fundamental role in the β-oxidation of fatty acids, has been recently identified as a modulator of immune function, although the mechanisms that underlie this role remain to be clarified. In this study, we addressed the modulation of l-carnitine transport and expression of related transporters during differentiation of human monocytes to macrophages. Whereas monocytes display a modest uptake of l-carnitine, GM-CSF-induced differentiation massively increased the saturable Na+-dependent uptake of l-carnitine. Kinetic and inhibition analyses demonstrate that in macrophage l-carnitine transport is mediated by a high-affinity component (Km∼4 µM) that is identifiable with the operation of OCTN2 transporter and a low-affinity component (Km> 10 mM) that is identifiable with system A for neutral amino acids. Consistently, both SLC22A5/OCTN2 and SLC38A2/SNAT2 are induced during the differentiation of monocytes to macrophages at gene and protein levels. Elucidation of GM-CSF signaling demonstrates that the cytokine causes the activation of mTOR kinase, leading to the phosphorylation and activation of STAT3, which, in turn, is responsible for OCTN2 transcription. SLC22A5/OCTN2 therefore emerges as a novel member of the set of genes markers of macrophage differentiation.
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Ingoglia
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Visigalli
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, Italy.
authors.forename: Bianca Maria
authors.initials: BM
authors.lastname: Rotoli
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, Italy.
authors.forename: Amelia
authors.initials: A
authors.lastname: Barilli
authors.affiliation: Department of Preclinical Pharmacokinetics, Biochemistry, and Metabolism, Chiesi Farmaceutici, Parma, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Riccardi
authors.affiliation: Department of Preclinical Pharmacokinetics, Biochemistry, and Metabolism, Chiesi Farmaceutici, Parma, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Puccini
authors.affiliation: Department of Preclinical Pharmacokinetics, Biochemistry, and Metabolism, Chiesi Farmaceutici, Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Milioli
authors.affiliation: Department of Preclinical Pharmacokinetics, Biochemistry, and Metabolism, Chiesi Farmaceutici, Parma, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Di Lascia
authors.affiliation: Immunohematology and Transfusion Centre, Department of Laboratory Medicine and Pathology, University Hospital of Parma, Parma, Italy.
authors.forename: Gino
authors.initials: G
authors.lastname: Bernuzzi
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, Italy; valeria.dallasta@unipr.it.
authors.forename: Valeria
authors.initials: V
authors.lastname: Dall'Asta
mesh_terms: D001692:Biological Transport; D002331:Carnitine / Q000378:metabolism*; D002454:Cell Differentiation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000074058:Solute Carrier Family 22 Member 5; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors
chemical_list: D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; C492020:SLC22A5 protein, human; D050796:STAT3 Transcription Factor; D000074058:Solute Carrier Family 22 Member 5; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D058570:TOR Serine-Threonine Kinases; D002331:Carnitine
keywords: GM-CSF; monocytes; rapamycin