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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Medzhitov, R. & Janeway, C. Jr Innate immunity. N. Engl. J. Med. 343, 338–344 (2000).
Hoffmann, J. A., Kafatos, F. C., Janeway, C. A. & Ezekowitz, R. A. Phylogenetic perspectives in innate immunity. Science 284, 1313–1318 (1999).
Aderem, A. & Ulevitch, R. J. Toll-like receptors in the induction of the innate immune response. Nature 406, 782–787 (2000).
Beutler, B. Endotoxin, toll-like receptor 4, and the afferent limb of innate immunity. Curr. Opin. Microbiol. 3, 23–28 (2000).
Bone, R. C. The pathogenesis of sepsis. Ann. Intern. Med. 115, 457–469 (1991).
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).
Morrison, D. C. & Ryan, J. L. Endotoxins and disease mechanisms. Annu. Rev. Med. 38, 417–432 (1987).
Tracey, K. J. et al. Shock and tissue injury induced by recombinant human cachectin. Science 234, 470–474 (1986).
Glauser, M. P., Zanetti, G., Baumgartner, J. D. & Cohen, J. Septic shock: pathogenesis. Lancet 338, 732–736 (1991).
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).
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).
Wang, H. et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285, 248–251 (1999).
Bernhagen, J. et al. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365, 756–759 (1993).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Calandra, T. et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nature Med. 6, 164–170 (2000).
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).
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).
Facchetti, F. et al. Suppurative granulomatous lymphadenitis. Immunohistochemical evidence for a B-cell-associated granuloma. Am. J. Surg. Pathol. 16, 955–961 (1992).
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.
About this article
HIV and HCV augments inflammatory responses through increased TREM-1 expression and signaling in Kupffer and Myeloid cells
PLOS Pathogens (2019)
Oxidized Low-Density Lipoprotein (Ox-LDL) and Triggering Receptor-Expressed Myeloid Cell (TREM-1) Levels Are Associated with Cardiometabolic Risk in Nonobese, Clinically Healthy, and Young Adults
Oxidative Medicine and Cellular Longevity (2019)
Markers Involved in Innate Immunity and Neutrophil Activation are Elevated during Acute Human Anaphylaxis: Validation of a Microarray Study
Journal of Innate Immunity (2019)
Rheumatoid arthritis synovial fibroblasts promote TREM-1 expression in monocytes via COX-2/PGE2 pathway
Arthritis Research & Therapy (2019)
Lack of an Association between the Functional Polymorphism TREM-1 rs2234237 and the Clinical Course of Sepsis among Critically Ill Caucasian Patients—A Monocentric Prospective Genetic Association Study
Journal of Clinical Medicine (2019)