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TREM-1 amplifies inflammation and is a crucial mediator of septic shock

Nature volume 410, pages 1103–1107 (2001)Cite this article

Abstract

Host innate responses to bacterial infections are primarily mediated by neutrophils and monocytes/macrophages1,2. These cells express pattern recognition receptors (PRRs) that bind conserved molecular structures shared by groups of microorganisms3,4. Stimulation of PRR signalling pathways initiates secretion of proinflammatory mediators3,4, which promote the elimination of infectious agents and the induction of tissue repair. Excessive inflammation owing to bacterial infections can lead to tissue damage and septic shock5,6,7,8,9. Here we show that inflammatory responses to microbial products are amplified by a pathway mediated by triggering receptor expressed on myeloid cells (TREM)-1. TREM-1 is an activating receptor expressed at high levels on neutrophils and monocytes that infiltrate human tissues infected with bacteria. Furthermore, it is upregulated on peritoneal neutrophils of patients with microbial sepsis and mice with experimental lipopolysaccaride (LPS)-induced shock. Notably, blockade of TREM-1 protects mice against LPS-induced shock, as well as microbial sepsis caused by live Escherichia coli or caecal ligation and puncture. These results demonstrate a critical function of TREM-1 in acute inflammatory responses to bacteria and implicate TREM-1 as a potential therapeutic target for septic shock.

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Figure 1: Regulation of human TREM-1 surface expression and function in vitro.
Figure 2: Human TREM-1 is strongly expressed in acute inflammatory lesions caused by bacteria and fungi.
Figure 3: Human TREM-1 is only weakly expressed in neutrophils and monocytes accumulating in non-microbial inflammations.
Figure 4: TREM-1 is strongly upregulated on peritoneal neutrophils during septic shock in humans and mice.
Figure 5: Inhibition of mTREM-1 signalling blocks endotoxic shock and inflammatory responses in vivo. a, C57BL/6 mice were treated with control hIgG1 (filled circles) or mTREM-1/IgG1 (open circles) 1 h before LPS administration.
Figure 6: TREM-1 is protective in bacterial peritonitis.

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Acknowledgements

We thank R. Breitkreutz and A. Benner for statistical analysis; O. Alebardi and S. Festa for technical assistance in immunohistochemistry; N. Schmitz for advice during mouse experiments; M. Cella, R. Ettinger, F. McBlane, M. Kopf, F. Sinigaglia and R. Torres for reviewing the manuscript; and P. Krammer for discussion. This work was partly supported by a BIOMED-2 grant to F.F. The Basel Institute for Immunology was founded and is supported by F. Hoffmann-La Roche, CH-4002 Basel.

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Author notes

  1. Fabio Facchetti and Markus A. Weigand: These authors contributed equally to this work

Authors and Affiliations

  1. Basel Institute for Immunology, Grenzacherstrasse 487, Basel, CH-4005, Switzerland

    Axel Bouchon & Marco Colonna

  2. Institute of Pathology, University of Brescia, Spedali Civili 1, Brescia, Italy

    Fabio Facchetti

  3. Clinic of Anaesthesiology, University of Heidelberg and Tumor Immunology Program, German Cancer Research Institute, (DKFZ), INF 110,280, Heidelberg, 69120, Germany

    Markus A. Weigand

Authors
  1. Axel Bouchon
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  4. Marco Colonna
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Correspondence to Marco Colonna.

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Bouchon, A., Facchetti, F., Weigand, M. et al. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature 410, 1103–1107 (2001). https://doi.org/10.1038/35074114

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