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

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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References

  1. 1

    Medzhitov, R. & Janeway, C. Jr Innate immunity. N. Engl. J. Med. 343, 338–344 (2000).

    CAS  PubMed  Google Scholar 

  2. 2

    Hoffmann, J. A., Kafatos, F. C., Janeway, C. A. & Ezekowitz, R. A. Phylogenetic perspectives in innate immunity. Science 284, 1313–1318 (1999).

    ADS  CAS  Article  Google Scholar 

  3. 3

    Aderem, A. & Ulevitch, R. J. Toll-like receptors in the induction of the innate immune response. Nature 406, 782–787 (2000).

    CAS  Article  Google Scholar 

  4. 4

    Beutler, B. Endotoxin, toll-like receptor 4, and the afferent limb of innate immunity. Curr. Opin. Microbiol. 3, 23–28 (2000).

    CAS  Article  Google Scholar 

  5. 5

    Bone, R. C. The pathogenesis of sepsis. Ann. Intern. Med. 115, 457–469 (1991).

    CAS  Article  Google Scholar 

  6. 6

    Beutler, B., Milsark, I. W. & Cerami, A. C. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 229, 869–871 (1985).

    ADS  CAS  Article  Google Scholar 

  7. 7

    Morrison, D. C. & Ryan, J. L. Endotoxins and disease mechanisms. Annu. Rev. Med. 38, 417–432 (1987).

    CAS  Article  Google Scholar 

  8. 8

    Tracey, K. J. et al. Shock and tissue injury induced by recombinant human cachectin. Science 234, 470–474 (1986).

    ADS  CAS  Article  Google Scholar 

  9. 9

    Glauser, M. P., Zanetti, G., Baumgartner, J. D. & Cohen, J. Septic shock: pathogenesis. Lancet 338, 732–736 (1991).

    CAS  Article  Google Scholar 

  10. 10

    Bouchon, A., Dietrich, J. & Colonna, M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J. Immunol. 164, 4991–4995 (2000).

    CAS  Article  Google Scholar 

  11. 11

    Lanier, L. L., Corliss, B. C., Wu, J., Leong, C. & Phillips, J. H. Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391, 703–707 (1998).

    ADS  CAS  Article  Google Scholar 

  12. 12

    Wang, H. et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285, 248–251 (1999).

    CAS  Article  Google Scholar 

  13. 13

    Bernhagen, J. et al. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365, 756–759 (1993).

    ADS  CAS  Article  Google Scholar 

  14. 14

    Ohlsson, K., Bjork, P., Bergenfeldt, M., Hageman, R. & Thompson, R. C. Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature 348, 550–552 (1990).

    ADS  CAS  Article  Google Scholar 

  15. 15

    Alexander, H. R., Doherty, G. M., Buresh, C. M., Venzon, D. J. & Norton, J. A. A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice. J. Exp. Med. 173, 1029–1032 (1991).

    CAS  Article  Google Scholar 

  16. 16

    Cella, M. et al. A novel inhibitory receptor (ILT3) expressed on monocytes, macrophages, and dendritic cells involved in antigen processing. J. Exp. Med. 185, 1743–1751 (1997).

    CAS  Article  Google Scholar 

  17. 17

    Echtenacher, B., Falk, W., Mannel, D. N. & Krammer, P. H. Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis. J. Immunol. 145, 3762–3766 (1990).

    CAS  PubMed  Google Scholar 

  18. 18

    Echtenacher, B., Mannel, D. N. & Hultner, L. Critical protective role of mast cells in a model of acute septic peritonitis. Nature 381, 75–77 (1996).

    ADS  CAS  Article  Google Scholar 

  19. 19

    Malaviya, R., Ikeda, T., Ross, E. & Abraham, S. N. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-α. Nature 381, 77–80 (1996).

    ADS  CAS  Article  Google Scholar 

  20. 20

    Rothe, J. et al. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF- mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature 364, 798–802 (1993).

    ADS  CAS  Article  Google Scholar 

  21. 21

    Pfeffer, K. et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 73, 457–467 (1993).

    CAS  Article  Google Scholar 

  22. 22

    Peschon, J. J. et al. TNF receptor-deficient mice reveal divergent roles for p55 and p75 in several models of inflammation. J. Immunol. 160, 943–952 (1998).

    CAS  PubMed  Google Scholar 

  23. 23

    Eskandari, M. K. et al. Anti-tumor necrosis factor antibody therapy fails to prevent lethality after cecal ligation and puncture or endotoxemia. J. Immunol. 148, 2724–2730 (1992).

    CAS  PubMed  Google Scholar 

  24. 24

    Calandra, T. et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nature Med. 6, 164–170 (2000).

    CAS  Article  Google Scholar 

  25. 25

    Appelmelk, B. J. et al. Use of mucin and hemoglobin in experimental murine gram-negative bacteremia enhances the immunoprotective action of antibodies reactive with the lipopolysaccharide core region. Antonie Van Leeuwenhoek 52, 537–542 (1986).

    CAS  Article  Google Scholar 

  26. 26

    American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit. Care. Med. 20, 864–874 (1992).

    Article  Google Scholar 

  27. 27

    Facchetti, F. et al. Suppurative granulomatous lymphadenitis. Immunohistochemical evidence for a B-cell-associated granuloma. Am. J. Surg. Pathol. 16, 955–961 (1992).

    CAS  Article  Google Scholar 

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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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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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