title: GM-CSF and IL-3 Modulate Human Monocyte TNF-α Production and Renewal inIn VitroModels of Trained Immunity.
abstract: GM-CSF and IL-3 are hematopoietic cytokines that also modulate the effector functions of several immune cell subsets. In particular, GM-CSF and IL-3 exert a significant control on monocyte and macrophage effector functions, as assessed in experimental models of inflammatory and autoimmune diseases and also in human studies. Here, we sought to investigate the mechanisms and the extent to which GM-CSF and IL-3 modulate the pro-inflammatory, LPS-mediated, activation of human CD14+monocytes taking into account the new concept of trained immunity (i.e., the priming stimulus modulates the response to subsequent stimuli mainly by inducing chromatin remodeling and increased transcription at relevant genetic loci). We demonstrate that GM-CSF and IL-3 priming enhances TNF-α production upon subsequent LPS stimulation (short-term model of trained immunity) in a p38- and SIRT2-dependent manner without increasingTNFprimary transcript levels (a more direct measure of transcription), thus supporting a posttranscriptional regulation of TNF-α in primed monocytes. GM-CSF and IL-3 priming followed by 6 days of resting also results in increased TNF-α production upon LPS stimulation (long-term model of trained immunity). In this case, however, GM-CSF and IL-3 priming induces a c-Myc-dependent monocyte renewal and increase in cell number that is in turn responsible for heightened TNF-α production. Overall, our results provide insights to understand the biology of monocytes in health and disease conditions in which the hematopoietic cytokines GM-CSF and IL-3 play a role and also extend our knowledge of the cellular and molecular mechanisms of trained immunity.
authors.affiliation: Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Borriello
authors.affiliation: Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Iannone
authors.affiliation: Department of Translational Medical Sciences, University of Naples Federico II , Naples , Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Di Somma
authors.affiliation: Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Loffredo
authors.affiliation: Department of Translational Medical Sciences, University of Naples Federico II , Naples , Italy.
authors.forename: Eloise
authors.initials: E
authors.lastname: Scamardella
authors.affiliation: Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Galdiero
authors.affiliation: Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.
authors.forename: Gilda
authors.initials: G
authors.lastname: Varricchi
authors.affiliation: Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.
authors.forename: Francescopaolo
authors.initials: F
authors.lastname: Granata
authors.affiliation: Department of Translational Medical Sciences, University of Naples Federico II , Naples , Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Portella
authors.affiliation: Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy; Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), National Research Council (CNR), Naples, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Marone
keywords: GM-CSF; IL-3; TLR; immunometabolism; inflammation; innate immune memory; macrophage; monocyte