title: Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis.
abstract: Sepsis is a frequently fatal condition characterized by an uncontrolled and harmful host reaction to microbial infection. Despite the prevalence and severity of sepsis, we lack a fundamental grasp of its pathophysiology. Here we report that the cytokine interleukin-3 (IL-3) potentiates inflammation in sepsis. Using a mouse model of abdominal sepsis, we showed that innate response activator B cells produce IL-3, which induces myelopoiesis of Ly-6C(high) monocytes and neutrophils and fuels a cytokine storm. IL-3 deficiency protects mice against sepsis. In humans with sepsis, high plasma IL-3 levels are associated with high mortality even after adjusting for prognostic indicators. This study deepens our understanding of immune activation, identifies IL-3 as an orchestrator of emergency myelopoiesis, and reveals a new therapeutic target for treating sepsis.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Department of Visceral, Thoracic and Vascular Surgery, Technische Universität Dresden, Dresden, Germany. fswirski@mgh.harvard.edu georg.weber@uniklinikum-dresden.de.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Weber
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Chousterman
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Shun
authors.initials: S
authors.lastname: He
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Fenn
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Anzai
authors.affiliation: Department of Anesthesiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Brenner
authors.affiliation: Department of Anesthesiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Uhle
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Clinton S
authors.initials: CS
authors.lastname: Robbins
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Lorette
authors.initials: L
authors.lastname: Noiret
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, Technische Universität Dresden, Dresden, Germany.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Maier
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, Technische Universität Dresden, Dresden, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Zönnchen
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, Technische Universität Dresden, Dresden, Germany.
authors.forename: Nuh N
authors.initials: NN
authors.lastname: Rahbari
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, Technische Universität Dresden, Dresden, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schölch
authors.affiliation: Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Klotzsche-von Ameln
authors.affiliation: Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, Technische Universität Dresden, Dresden, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.affiliation: Department of Anesthesiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hofer
authors.affiliation: Department of Anesthesiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Weigand
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. fswirski@mgh.harvard.edu georg.weber@uniklinikum-dresden.de.
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation; D007377:Interleukin-3 / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008221:Lymphoid Tissue / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology; D038042:Myelopoiesis; D009504:Neutrophils / Q000276:immunology; D010538:Peritonitis / Q000276:immunology / Q000473:pathology; D011379:Prognosis; D018805:Sepsis / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy
chemical_list: D016207:Cytokines; C508596:IL3 protein, human; D007377:Interleukin-3; D008070:Lipopolysaccharides