Z Gastroenterol 2016; 54 - PP1
DOI: 10.1055/s-0036-1582059

Interleukin-3 amplifies acute inflammation in sepsis

GF Weber 1, 2, BG Chousterman 2, S He 2, AM Fenn 2, M Nairz 2, A Anzai 2, T Brenner 3, F Uhle 3, Y Iwamoto 2, CS Robbins 2, L Noiret 2, SL Maier 6, T Zönnchen 6, NN Rahbari 6, S Schölch 6, A Klotzsche-von Ameln 4, T Chavakis 4, J Weitz 6, S Hofer 3, MA Weigand 3, M Nahrendorf 2, R Weissleder 2, 5, FK Swirski 2
  • 1Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen
  • 2Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  • 3Department of Anesthesiology, University of Heidelberg, Heidelberg
  • 4Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden
  • 5Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 6Department of Visceral, Thoracic and Vascular Surgery, Universitätsklinikum Dresden, Technische Universität Dresden, Dresden

Purpose: Sepsis is a frequently fatal condition characterized by an uncontrolled host reaction to microbial infection claiming millions of lives world wide every year. In the initial, inflammatory phase, the immune system overproduces cytokine-secreting leukocytes that can cause organ damage and death. Recent clinical trials targeting inflammatory mediators have failed, reflecting an urgent need for a better fundamental understanding of sepsis' pathophysiology.

Methods: In a translational approach we subjected IL-3-/- and wild type (wt) mice to Cecal Ligation and Puncture (CLP), a mouse model of experimental sepsis. After extensive in vivo and ex vivo phenotyping we enumerated the emergency myelopoiesis using in vivo adoptive transfer and in vitro experiments. We identified the source of interleukin (IL)-3 using flow cytometric, RT-PCR and immunofluorescence analysis. Finally, we determined the importance of Interleukin-3 in human sepsis in an independent retrospective and prospective clinical trial.

Results: Here we show that IL-3 is an essential inducer of inflammation in sepsis. We show that innate response activator (IRA) B cell produced IL-3 amplifies myelopoiesis of Ly-6Chigh monocytes and neutrophils, and potentiates the cytokine storm in sepsis. Compared to IL-3-/- mice, wt animals develop multi-organ damage and succumb to infection more rapidly and in larger numbers. In patients with sepsis, high plasma IL-3 levels associate with high mortality even after adjusting for prognostic indicators.

Conclusions: Altogether, this study enriches our understanding of immune activation, and identifies IL-3 as an orchestrator of emergency hematopoiesis and potential therapeutic target for the treatment of sepsis.

Reference:

Weber et al., Science 2015 Mar 13;347(6227):1260 – 5.

*Contributed equally to this manuscript.