title: DUSP3 Genetic Deletion Confers M2-like Macrophage-Dependent Tolerance to Septic Shock.
abstract: DUSP3 is a small dual-specificity protein phosphatase with an unknown physiological function. We report that DUSP3 is strongly expressed in human and mouse monocytes and macrophages, and that its deficiency in mice promotes tolerance to LPS-induced endotoxin shock and to polymicrobial septic shock after cecal ligation and puncture. By using adoptive transfer experiments, we demonstrate that resistance to endotoxin is macrophage dependent and transferable, and that this protection is associated with a striking increase of M2-like macrophages in DUSP3(-/-) mice in both the LPS and cecal ligation and puncture models. We show that the altered response of DUSP3(-/-) mice to sepsis is reflected in decreased TNF production and impaired ERK1/2 activation. Our results demonstrate that DUSP3 plays a key and nonredundant role as a regulator of innate immune responses by mechanisms involving the control of ERK1/2 activation, TNF secretion, and macrophage polarization.
authors: Laboratory of Immunology and Infectious Diseases, GIGA-Signal Transduction Unit, University of Liège, B-4000 Liège, Belgium;
authors: Pratibha
authors: P
authors: Singh
authors: Inflammation Research Center, VIB, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, B-9000 Ghent, Belgium;
authors: Lien
authors: L
authors: Dejager
authors: Laboratory of Immunology and Infectious Diseases, GIGA-Signal Transduction Unit, University of Liège, B-4000 Liège, Belgium;
authors: Mathieu
authors: M
authors: Amand
authors: Laboratory of Animal Genomics, GIGA-Genetics Unit, University of Liège, B-4000 Liège, Belgium;
authors: Emilie
authors: E
authors: Theatre
authors: Laboratory of Immunology and Infectious Diseases, GIGA-Signal Transduction Unit, University of Liège, B-4000 Liège, Belgium;
authors: Maud
authors: M
authors: Vandereyken
authors: Laboratory of Immunology and Infectious Diseases, GIGA-Signal Transduction Unit, University of Liège, B-4000 Liège, Belgium;
authors: Tinatin
authors: T
authors: Zurashvili
authors: Laboratory of Immunology and Infectious Diseases, GIGA-Signal Transduction Unit, University of Liège, B-4000 Liège, Belgium;
authors: Maneesh
authors: M
authors: Singh
authors: Department of Internal Medicine II, University Hospital Regensburg, 93042 Regensburg, Germany;
authors: Matthias
authors: M
authors: Mack
authors: Inflammation Research Center, VIB, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, B-9000 Ghent, Belgium;
authors: Steven
authors: S
authors: Timmermans
authors: Laboratory of Immunology and Infectious Diseases, GIGA-Signal Transduction Unit, University of Liège, B-4000 Liège, Belgium;
authors: Lucia
authors: L
authors: Musumeci
authors: Laboratory of Molecular Immunology and Signal Transduction, GIGA-Signal Transduction Unit, University of Liège, B-4000 Liège, Belgium;
authors: Emmanuel
authors: E
authors: Dejardin
authors: Signal Transduction Program, Sanford-Burnham Institute, La Jolla, CA 92037; MedImmune, Gaithersburg, MD 20878;
authors: Tomas
authors: T
authors: Mustelin
authors: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, B-1050 Brussels, Belgium; Myeloid Cell Immunology Laboratory, VIB, B-1050 Brussels, Belgium; and.
authors: Jo A
authors: JA
authors: Van Ginderachter
authors: Laboratory of Immunology and Infectious Diseases, GIGA-Signal Transduction Unit, University of Liège, B-4000 Liège, Belgium;
authors: Michel
authors: M
authors: Moutschen
authors: Laboratory of Thrombosis and Hemostasis, GIGA-Cardiovascular Sciences Unit, University of Liège, B-4000 Liège, Belgium.
authors: Cécile
authors: C
authors: Oury
authors: Inflammation Research Center, VIB, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, B-9000 Ghent, Belgium;
authors: Claude
authors: C
authors: Libert
authors: Laboratory of Immunology and Infectious Diseases, GIGA-Signal Transduction Unit, University of Liège, B-4000 Liège, Belgium; srahmouni@ulg.ac.be.
authors: Souad
authors: http://orcid.org/0000-0003-0956-0242
authors: S
authors: Rahmouni
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015153:Blotting, Western; D054640:Dual Specificity Phosphatase 3 / Q000172:deficiency / Q000276:immunology*; D005434:Flow Cytometry; D017353:Gene Deletion; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012772:Shock, Septic / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: C517025:DUSP3 protein, human; D054640:Dual Specificity Phosphatase 3; C517026:Dusp3 protein, mouse