Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The TREM receptor family and signal integration

Abstract

TREM proteins are a family of cell surface receptors that participate in diverse cell processes, including inflammation, bone homeostasis, neurological development and coagulation. TREM-1, the first to be identified, acts to amplify inflammation. Other TREM proteins regulate the differentiation and function of macrophages, microglia, dendritic cells, osteoclasts and platelets. Here we discuss the state of the field, putative ligands of TREM proteins and the challenges that remain in understanding TREM biology.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Human and mouse gene clusters encoding TREM molecules.
Figure 2: TREM-1 and sTREM-1 in inflammation.
Figure 3: Multiple functions of TREM-2.
Figure 4: Hypothetical model of a TREM-2 receptor complex.

Similar content being viewed by others

References

  1. 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  PubMed  Google Scholar 

  2. Daws, M.R., Lanier, L.L., Seaman, W.E. & Ryan, J.C. Cloning and characterization of a novel mouse myeloid DAP12-associated receptor family. Eur. J. Immunol. 31, 783–791 (2001).

    CAS  PubMed  Google Scholar 

  3. Chung, D.H., Seaman, W.E. & Daws, M.R. Characterization of TREM-3, an activating receptor on mouse macrophages: definition of a family of single Ig domain receptors on mouse chromosome 17. Eur. J. Immunol. 32, 59–66 (2002).

    CAS  PubMed  Google Scholar 

  4. Gordon, S. & Taylor, P.R. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5, 953–964 (2005).

    CAS  PubMed  Google Scholar 

  5. Schmid, C.D. et al. Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J. Neurochem. 83, 1309–1320 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Sessa, G. et al. Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia. Eur. J. Neurosci. 20, 2617–2628 (2004).

    PubMed  Google Scholar 

  7. Bouchon, A., Hernandez-Munain, C., Cella, M. & Colonna, M.A. DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J. Exp. Med. 194, 1111–1122 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Paloneva, J. et al. TREM-2 mutations in presenile dementia, PLOSL. Am. J. Hum. Genet. 71, 656–662 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Paloneva, J. et al. DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. J. Exp. Med. 198, 669–675 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Cella, M. et al. Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J. Exp. Med. 198, 645–651 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Washington, A.V., Quigley, L. & McVicar, D.W. Initial characterization of TREM-like transcript (TLT)-1: a putative inhibitory receptor within the TREM cluster. Blood 100, 3822–3824 (2002).

    CAS  PubMed  Google Scholar 

  12. Allcock, R.J., Barrow, A.D., Forbes, S., Beck, S. & Trowsdale, J. The human TREM gene cluster at 6p21.1 encodes both activating and inhibitory single IgV domain receptors and includes NKp44. Eur. J. Immunol. 33, 567–577 (2003).

    CAS  PubMed  Google Scholar 

  13. Clark, G.J., Green, B.J. & Hart, D.N. The CMRF-35H gene structure predicts for an independently expressed member of an ITIM/ITAM pair of molecules localized to human chromosome 17. Tissue Antigens 55, 101–109 (2000).

    CAS  PubMed  Google Scholar 

  14. Green, B.J., Clark, G.J. & Hart, D.N. The CMRF-35 mAb recognizes a second leukocyte membrane molecule with a domain similar to the poly Ig receptor. Int. Immunol. 10, 891–899 (1998).

    CAS  PubMed  Google Scholar 

  15. Aguilar, H. et al. Molecular characterization of a novel immune receptor restricted to the monocytic lineage. J. Immunol. 173, 6703–6711 (2004).

    CAS  PubMed  Google Scholar 

  16. Chung, D.H. et al. CMRF-35-like molecule-1, a novel mouse myeloid receptor, can inhibit osteoclast formation. J. Immunol. 171, 6541–6548 (2003).

    CAS  PubMed  Google Scholar 

  17. Jackson, D.G., Hart, D.N., Starling, G. & Bell, J.I. Molecular cloning of a novel member of the immunoglobulin gene superfamily homologous to the polymeric immunoglobulin receptor. Eur. J. Immunol. 22, 1157–1163 (1992).

    CAS  PubMed  Google Scholar 

  18. Viertlboeck, B.C., Schmitt, R. & Göbel, T.W. The chicken immunoregulatory receptor families SIRP, TREM, and CMRF35/CD300L. Immunogenetics 58, 180–190 (2006).

    CAS  PubMed  Google Scholar 

  19. Stet, R.J. et al. Novel immunoglobulin-like transcripts in teleost fish encode polymorphic receptors with cytoplasmic ITAM or ITIM and a new structural Ig domain similar to the natural cytotoxicity receptor NKp44. Immunogenetics 57, 77–89 (2005).

    CAS  PubMed  Google Scholar 

  20. Radaev, S., Kattah, M., Rostro, B., Colonna, M. & Sun, P.D. Crystal structure of the human myeloid cell activating receptor TREM-1. Structure 11, 1527–1535 (2003).

    CAS  PubMed  Google Scholar 

  21. Kelker, M.S. et al. Crystal structure of human triggering receptor expressed on myeloid cells 1 (TREM-1) at 1.47 A. J. Mol. Biol. 342, 1237–1248 (2004).

    CAS  PubMed  Google Scholar 

  22. Kelker, M.S., Debler, E.W. & Wilson, I.A. Crystal structure of mouse triggering receptor expressed on myeloid cells 1 (TREM-1) at 1.76 A. J. Mol. Biol. 344, 1175–1181 (2004).

    CAS  PubMed  Google Scholar 

  23. Gattis, J.L. et al. The structure of the extracellular domain of triggering receptor expressed on myeloid cells like transcript-1 and evidence for a naturally occurring soluble fragment. J. Biol. Chem. 281, 13396–13403 (2006).

    CAS  PubMed  Google Scholar 

  24. Vivier, E., Nunes, J.A. & Vely, F. Natural killer cell signaling pathways. Science 306, 1517–1519 (2004).

    CAS  Google Scholar 

  25. McVicar, D.W. & Burshtyn, D.N. Intracellular signaling by the killer immunoglobulin-like receptors and Ly49. Sci. STKE 2001, RE1 (2001).

    CAS  PubMed  Google Scholar 

  26. Lanier, L.L. Natural killer cell receptor signaling. Curr. Opin. Immunol. 15, 308–314 (2003).

    CAS  PubMed  Google Scholar 

  27. Hamerman, J.A. et al. Cutting edge: Inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J. Immunol. 177, 2051–2055 (2006).

    CAS  PubMed  Google Scholar 

  28. Turnbull, I.R. et al. Cutting edge: TREM-2 attenuates macrophage activation. J. Immunol. 177, 3520–3524 (2006).

    CAS  PubMed  Google Scholar 

  29. Hamerman, J.A. & Lanier, L.L. Inhibition of immune responses by ITAM-bearing receptors. Sci. STKE 2006, re1 (2006).

    PubMed  Google Scholar 

  30. Blasius, A.L. & Colonna, M. Sampling and signaling in plasmacytoid dendritic cells: the potential roles of Siglec-H. Trends Immunol. 27, 255–260 (2006).

    CAS  PubMed  Google Scholar 

  31. Barrow, A.D. & Trowsdale, J. You say ITAM and I say ITIM, let's call the whole thing off: the ambiguity of immunoreceptor signalling. Eur. J. Immunol. 36, 1646–1653 (2006).

    CAS  PubMed  Google Scholar 

  32. Washington, A.V., Quigley, L. & McVicar, D.W. Initial characterization of TREM-like transcript (TLT)-1: a putative inhibitory receptor within the TREM cluster. Triggering receptors expressed on myeloid cells. Blood 100, 3822–3824 (2002).

    CAS  PubMed  Google Scholar 

  33. Barrow, A.D. et al. Cutting edge: TREM-like transcript-1, a platelet immunoreceptor tyrosine-based inhibition motif encoding costimulatory immunoreceptor that enhances, rather than inhibits, calcium signaling via SHP-2. J. Immunol. 172, 5838–5842 (2004).

    CAS  PubMed  Google Scholar 

  34. Bouchon, A., Facchetti, F., Weigand, M.A. & Colonna, M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature 410, 1103–1107 (2001).

    CAS  PubMed  Google Scholar 

  35. Nathan, C. & Ding, A. TREM-1: a new regulator of innate immunity in sepsis syndrome. Nat. Med. 7, 530–532 (2001).

    CAS  PubMed  Google Scholar 

  36. Bleharski, J.R. et al. A role for triggering receptor expressed on myeloid cells-1 in host defense during the early-induced and adaptive phases of the immune response. J. Immunol. 170, 3812–3818 (2003).

    CAS  PubMed  Google Scholar 

  37. Netea, M.G. et al. Triggering receptor expressed on myeloid cells-1 (TREM-1) amplifies the signals induced by the NACHT-LRR (NLR) pattern recognition receptors. J. Leukocyte Biol. (in the press).

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

    CAS  PubMed  Google Scholar 

  39. Yang, H., Wang, H. & Tracey, K.J. HMG-1 rediscovered as a cytokine. Shock 15, 247–253 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  41. Bozza, M. et al. Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J. Exp. Med. 189, 341–346 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Dinarello, C.A. Proinflammatory cytokines. Chest 118, 503–508 (2000).

    CAS  PubMed  Google Scholar 

  43. Riewald, M., Petrovan, R.J., Donner, A., Mueller, B.M. & Ruf, W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296, 1880–1882 (2002).

    CAS  PubMed  Google Scholar 

  44. Cohen, J. The immunopathogenesis of sepsis. Nature 420, 885–891 (2002).

    CAS  PubMed  Google Scholar 

  45. Turnbull, I.R. et al. DAP12 (KARAP) amplifies inflammation and increases mortality from endotoxemia and septic peritonitis. J. Exp. Med. 202, 363–369 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Gibot, S. et al. A soluble form of the triggering receptor expressed on myeloid cells-1 modulates the inflammatory response in murine sepsis. J. Exp. Med. 200, 1419–1426 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Agarwal, P.K. & Kumari, R. Sepsis–theory and therapies. N. Engl. J. Med. 348, 1600–1602 (2003).

    PubMed  Google Scholar 

  48. Mohamadzadeh, M. et al. Activation of triggering receptor expressed on myeloid cells-1 on human neutrophils by marburg and ebola viruses. J. Virol. 80, 7235–7244 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu-Bryan, R. & Terkeltaub, R. Evil humors take their toll as innate immunity makes gouty joints TREM-ble. Arthritis Rheum. 54, 383–386 (2006).

    CAS  PubMed  Google Scholar 

  50. Murakami, Y. et al. Induction of triggering receptor expressed on myeloid cells 1 in murine resident peritoneal macrophages by monosodium urate monohydrate crystals. Arthritis Rheum. 54, 455–462 (2006).

    CAS  PubMed  Google Scholar 

  51. Gibot, S. et al. Soluble triggering receptor expressed on myeloid cells and the diagnosis of pneumonia. N. Engl. J. Med. 350, 451–458 (2004).

    CAS  PubMed  Google Scholar 

  52. Gibot, S. et al. Plasma level of a triggering receptor expressed on myeloid cells-1: its diagnostic accuracy in patients with suspected sepsis. Ann. Intern. Med. 141, 9–15 (2004).

    CAS  PubMed  Google Scholar 

  53. Koussoulas, V. et al. Soluble triggering receptor expressed on myeloid cells (sTREM-1): a new mediator involved in the pathogenesis of peptic ulcer disease. Eur. J. Gastroenterol. Hepatol. 18, 375–379 (2006).

    PubMed  Google Scholar 

  54. Schenk, M., Bouchon, A., Birrer, S., Colonna, M. & Mueller, C. Macrophages expressing triggering receptor expressed on myeloid cells-1 are underrepresented in the human intestine. J. Immunol. 174, 517–524 (2005).

    CAS  PubMed  Google Scholar 

  55. Tzivras, M. & et al. Role of soluble triggering receptor expressed on myeloid cells in inflammatory bowel disease. World J. Gastroenterol. 12, 3416–3419 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Nochi, H. et al. Modulation of hepatic granulomatous responses by transgene expression of DAP12 or TREM-1-Ig molecules. Am. J. Pathol. 162, 1191–1201 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Mahdy, A.M. et al. Production of soluble triggering receptor expressed on myeloid cells by lipopolysacccharide-stimulated human neutrophils involves de novo protein synthesis. Clin. Vaccine Immunol. 13, 492–495 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Gingras, M.C., Lapillonne, H. & Margolin, J.F. TREM-1, MDL-1, and DAP12 expression is associated with a mature stage of myeloid development. Mol. Immunol. 38, 817–824 (2002).

    CAS  PubMed  Google Scholar 

  59. Begum, N.A. et al. Mycobacterium bovis BCG cell wall-specific differentially expressed genes identified by differential display and cDNA subtraction in human macrophages. Infect. Immun. 72, 937–948 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Tanaka, J. Nasu-Hakola disease: a review of its leukoencephalopathic and membranolipodystrophic features. Neuropathology 20, S25–S29 (2000).

    PubMed  Google Scholar 

  61. Verloes, A. et al. Nasu-Hakola syndrome: polycystic lipomembranous osteodysplasia with sclerosing leucoencephalopathy and presenile dementia. J. Med. Genet. 34, 753–757 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Kitajima, I. et al. Nasu-Hakola disease (membranous lipodystrophy). Clinical, histopathological and biochemical studies of three cases. J. Neurol. Sci. 91, 35–52 (1989).

    CAS  PubMed  Google Scholar 

  63. Paloneva, J. et al. Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat. Genet. 25, 357–361 (2000).

    CAS  PubMed  Google Scholar 

  64. Kondo, T. et al. Heterogeneity of presenile dementia with bone cysts (Nasu-Hakola disease): Three genetic forms. Neurology 59, 1105–1107 (2002).

    CAS  PubMed  Google Scholar 

  65. Teitelbaum, S.L. Bone resorption by osteoclasts. Science 289, 1504–1508 (2000).

    CAS  PubMed  Google Scholar 

  66. Kaifu, T. et al. Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J. Clin. Invest. 111, 323–332 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Koga, T. et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428, 758–763 (2004).

    CAS  PubMed  Google Scholar 

  68. Walsh, M.C. et al. Osteoimmunology: interplay between the immune system and bone metabolism. Annu. Rev. Immunol. 24, 33–63 (2006).

    CAS  PubMed  Google Scholar 

  69. Humphrey, M.B. et al. The signaling adapter protein DAP12 regulates multinucleation during osteoclast development. J. Bone Miner. Res. 19, 224–234 (2004).

    CAS  PubMed  Google Scholar 

  70. Faccio, R., Zou, W., Colaianni, G., Teitelbaum, S.L. & Ross, F.P. High dose M-CSF partially rescues the Dap12−/− osteoclast phenotype. J. Cell. Biochem. 90, 871–883 (2003).

    CAS  PubMed  Google Scholar 

  71. Nataf, S. et al. Brain and bone damage in KARAP/DAP12 loss-of-function mice correlate with alterations in microglia and osteoclast lineages. Am. J. Pathol. 166, 275–286 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Humphrey, M.B. et al. TREM2, a DAP12-associated receptor, regulates osteoclast differentiation and function. J. Bone Miner. Res. 21, 237–245 (2006).

    CAS  PubMed  Google Scholar 

  73. Takahashi, K., Rochford, C.D.P. & Neumann, H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 201, 647–657 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Hamerman, J.A., Tchao, N.K., Lowell, C.A. & Lanier, L.L. Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nat. Immunol. 6, 579–586 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Aoki, N., Zganiacz, A., Margetts, P. & Xing, Z. Differential regulation of DAP12 and molecules associated with DAP12 during host responses to mycobacterial infection. Infect. Immun. 72, 2477–2483 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Barrow, A.D. et al. Cutting edge: TREM-like transcript-1, a platelet immunoreceptor tyrosine-based inhibition motif encoding costimulatory immunoreceptor that enhances, rather than inhibits, calcium signaling via SHP-2. J. Immunol. 172, 5838–5842 (2004).

    CAS  PubMed  Google Scholar 

  77. Washington, A.V. et al. A TREM family member, TLT-1, is found exclusively in the alpha-granules of megakaryocytes and platelets. Blood 104, 1042–1047 (2004).

    CAS  PubMed  Google Scholar 

  78. King, R.G., Herrin, B.R. & Justement, L.B. Trem-like transcript 2 is expressed on cells of the myeloid/granuloid and B lymphoid lineage and is up-regulated in response to inflammation. J. Immunol. 176, 6012–6021 (2006).

    CAS  PubMed  Google Scholar 

  79. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

    CAS  Google Scholar 

  80. Daws, M.R. et al. Pattern recognition by TREM-2: binding of anionic ligands. J. Immunol. 171, 594–599 (2003).

    CAS  PubMed  Google Scholar 

  81. Takegahara, N. et al. Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nat. Cell Biol. 8, 615–622 (2006).

    CAS  PubMed  Google Scholar 

  82. Tamagnone, L. & Giordano, S. Semaphorin pathways orchestrate osteogenesis. Nat. Cell Biol. 8, 545–547 (2006).

    CAS  PubMed  Google Scholar 

  83. Karpanen, T. et al. Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB J. 20, 1462–1472 (2006).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marco Colonna.

Ethics declarations

Competing interests

M.C. has stock options in BioXell, which works on TREM proteins

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klesney-Tait, J., Turnbull, I. & Colonna, M. The TREM receptor family and signal integration. Nat Immunol 7, 1266–1273 (2006). https://doi.org/10.1038/ni1411

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1411

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing