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Critical Care
Published in: Critical Care 1/2024

Open Access 01-12-2024 | Septicemia | Review

Triggering receptor expressed on myeloid cells-1 in sepsis, and current insights into clinical studies

Authors: Vivienne Theobald, Felix Carl Fabian Schmitt, Chiara Simone Middel, Lena Gaissmaier, Thorsten Brenner, Markus Alexander Weigand

Published in: Critical Care | Issue 1/2024

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Abstract

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor and plays a critical role in the immune response. TREM-1 activation leads to the production and release of proinflammatory cytokines, chemokines, as well as its own expression and circulating levels of the cleaved soluble extracellular portion of TREM-1 (sTREM-1). Because patients with sepsis and septic shock show elevated sTREM-1 levels, TREM-1 has attracted attention as an important contributor to the inadequate immune response in this often-deadly condition. Since 2001, when the first blockade of TREM-1 in sepsis was performed, many potential TREM-1 inhibitors have been established in animal models. However, only one of them, nangibotide, has entered clinical trials, which have yielded promising data for future treatment of sepsis, septic shock, and other inflammatory disease such as COVID-19. This review discusses the TREM-1 pathway and important ligands, and highlights the development of novel inhibitors as well as their clinical potential for targeted treatment of various inflammatory conditions.
Literature
1.
Bouchon A, Dietrich J, Colonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes1. J Immunol. 2000;164(10):4991–5.PubMedCrossRef
2.
François B, Lambden S, Fivez T, Gibot S, Derive M, Grouin JM, et al. Prospective evaluation of the efficacy, safety, and optimal biomarker enrichment strategy for nangibotide, a TREM-1 inhibitor, in patients with septic shock (ASTONISH): a double-blind, randomised, controlled, phase 2b trial. Lancet Respir Med. 2023.
3.
Bouchon A, Facchetti F, Weigand MA, Colonna M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature. 2001;410(6832):1103–7.PubMedCrossRef
4.
5.
Tammaro A, Derive M, Gibot S, Leemans JC, Florquin S, Dessing MC. TREM-1 and its potential ligands in non-infectious diseases: from biology to clinical perspectives. Pharmacol Ther. 2017;177:81–95.PubMedCrossRef
6.
Gulati A, Kaur D, Krishna Prasad GVR, Mukhopadhaya A. PRR function of innate immune receptors in recognition of bacteria or bacterial ligands. In: Chattopadhyay K, Basu SC, editors. Biochemical and biophysical roles of cell surface molecules. Singapore: Springer; 2018. p. 255–80.CrossRef
7.
Tammaro A, Kers J, Emal D, Stroo I, Teske GJD, Butter LM, et al. Effect of TREM-1 blockade and single nucleotide variants in experimental renal injury and kidney transplantation. Sci Rep. 2016;6(1):38275.PubMedPubMedCentralCrossRef
8.
9.
Dantas P, Matos AO, da Silva FE, Silva-Sales M, Sales-Campos H. Triggering receptor expressed on myeloid cells-1 (TREM-1) as a therapeutic target in infectious and noninfectious disease: a critical review. Int Rev Immunol. 2020;39(4):188–202.PubMedCrossRef
10.
11.
Gibot S, Massin F, Le Renard P, Béné MC, Faure GC, Bollaert PE, et al. Surface and soluble triggering receptor expressed on myeloid cells-1: expression patterns in murine sepsis. Crit Care Med. 2005;33(8):1787–93.PubMedCrossRef
12.
13.
Weber B, Schuster S, Zysset D, Rihs S, Dickgreber N, Schürch C, et al. TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance. PLoS Pathog. 2014;10(1): e1003900.PubMedPubMedCentralCrossRef
14.
François B, Wittebole X, Ferrer R, Mira JP, Dugernier T, Gibot S, et al. Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial. Intensive Care Med. 2020;46(7):1425–37.PubMedCrossRef
15.
Kelker MS, Foss TR, Peti W, Teyton L, Kelly JW, Wüthrich K, et al. Crystal structure of human triggering receptor expressed on myeloid Cells 1 (TREM-1) at 1.47Å. J Mol Biol. 2004;342(4):1237–48.PubMedCrossRef
16.
Radaev S, Kattah M, Rostro B, Colonna M, Sun PD. Crystal structure of the human myeloid cell activating receptor TREM-1. Structure. 2003;11(12):1527–35.PubMedCrossRef
17.
Allcock RJN, Barrow AD, 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. 2003;33(2):567–77.PubMedCrossRef
18.
Gibot S, Massin F. Soluble form of the triggering receptor expressed on myeloid cells 1: an anti-inflammatory mediator? Intensive Care Med. 2006;32(2):185–7.PubMedCrossRef
19.
20.
21.
Arts RJ, Joosten LA, van der Meer JW, Netea MG. TREM-1: intracellular signaling pathways and interaction with pattern recognition receptors. J Leukoc Biol. 2013;93(2):209–15.PubMedCrossRef
22.
Derive M, Bouazza Y, Sennoun N, Marchionni S, Quigley L, Washington V, et al. Soluble TREM-like transcript-1 regulates leukocyte activation and controls microbial sepsis. J Immunol. 2012;188(11):5585–92.PubMedCrossRef
23.
Read CB, Kuijper JL, Hjorth SA, Heipel MD, Tang X, Fleetwood AJ, et al. Cutting edge: identification of neutrophil PGLYRP1 as a ligand for TREM-1. J Immunol. 2015;194(4):1417–21.PubMedPubMedCentralCrossRef
24.
Kashyap DR, Wang M, Liu LH, Boons GJ, Gupta D, Dziarski R. Peptidoglycan recognition proteins kill bacteria by activating protein-sensing two-component systems. Nat Med. 2011;17(6):676–83.PubMedPubMedCentralCrossRef
25.
Sharapova TN, Romanova EA, Ivanova OK, Sashchenko LP, Yashin DV. Cytokines TNFα, IFNγ and IL-2 are responsible for signal transmission from the innate immunity protein Tag7 (PGLYRP1) to cytotoxic effector lymphocytes. Cells. 2020;9(12):2602.PubMedPubMedCentralCrossRef
26.
Sharapova TN, Ivanova OK, Soshnikova NV, Romanova EA, Sashchenko LP, Yashin DV. Innate immunity protein Tag7 induces 3 distinct populations of cytotoxic cells that use different mechanisms to exhibit their antitumor activity on human leukocyte antigen-deficient cancer cells. J Innate Immun. 2017;9(6):598–608.PubMedCrossRef
27.
Singh H, Rai V, Nooti SK, Agrawal DK. Novel ligands and modulators of triggering receptor expressed on myeloid cells receptor family: 2015–2020 updates. Expert Opin Ther Pat. 2021;31(6):549–61.PubMedPubMedCentralCrossRef
28.
Bustin M. Regulation of DNA-dependent activities by the functional motifs of the high-mobility-group chromosomal proteins. Mol Cell Biol. 1999;19(8):5237–46.PubMedPubMedCentralCrossRef
29.
Yang H, Antoine DJ, Andersson U, Tracey KJ. The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. J Leukoc Biol. 2013;93(6):865–73.PubMedPubMedCentralCrossRef
30.
Weigand MA, Hörner C, Bardenheuer HJ, Bouchon A. The systemic inflammatory response syndrome. Best Pract Res Clin Anaesthesiol. 2004;18(3):455–75.PubMedCrossRef
31.
Dong H, Zhang Y, Huang Y, Deng H. Pathophysiology of RAGE in inflammatory diseases. Frontiers Immunol. 2022;13:931473.CrossRef
32.
Wu J, Li J, Salcedo R, Mivechi NF, Trinchieri G, Horuzsko A. The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Cancer Res. 2012;72(16):3977–86.PubMedPubMedCentralCrossRef
33.
Wang X, Xiang L, Li H, Chen P, Feng Y, Zhang J, et al. The role of HMGB1 signaling pathway in the development and progression of hepatocellular carcinoma: a review. Int J Mol Sci. 2015;16(9):22527–40.PubMedPubMedCentralCrossRef
34.
Rosenzweig R, Nillegoda NB, Mayer MP, Bukau B. The Hsp70 chaperone network. Nat Rev Mol Cell Biol. 2019;20(11):665–80.PubMedCrossRef
35.
El Mezayen R, El Gazzar M, Seeds MC, McCall CE, Dreskin SC, Nicolls MR. Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin. Immunol Lett. 2007;111(1):36–44.PubMedPubMedCentralCrossRef
36.
Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med. 2000;6(4):435–42.PubMedCrossRef
37.
Sharapova TN, Romanova EA, Ivanova OK, Yashin DV, Sashchenko LP. Hsp70 interacts with the TREM-1 receptor expressed on monocytes and thereby stimulates generation of cytotoxic lymphocytes active against mhc-negative tumor cells. Int J Mol Sci. 2021;22(13):6889.PubMedPubMedCentralCrossRef
38.
Sudakov NP, Klimenkov IV, Byvaltsev VA, Nikiforov SB, Konstantinov YM. Extracellular actin in health and disease. Biochemistry (Mosc). 2017;82(1):1–12.PubMedCrossRef
39.
Haselmayer P, Grosse-Hovest L, von Landenberg P, Schild H, Radsak MP. TREM-1 ligand expression on platelets enhances neutrophil activation. Blood. 2007;110(3):1029–35.PubMedCrossRef
40.
Fu L, Han L, Xie C, Li W, Lin L, Pan S, et al. Identification of Extracellular Actin As a Ligand for Triggering Receptor Expressed on Myeloid Cells-1 Signaling. Front Immunol. 2017;8:917.PubMedPubMedCentralCrossRef
41.
Gibot S, Kolopp-Sarda MN, Béné MC, Bollaert PE, Lozniewski A, Mory F, et al. A soluble form of the triggering receptor expressed on myeloid cells-1 modulates the inflammatory response in murine sepsis. J Exp Med. 2004;200(11):1419–26.PubMedPubMedCentralCrossRef
42.
Qiang X, Yang WL, Wu R, Zhou M, Jacob A, Dong W, et al. Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat Med. 2013;19(11):1489–95.PubMedPubMedCentralCrossRef
43.
Denning NL, Aziz M, Murao A, Gurien SD, Ochani M, Prince JM, et al. Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsis. JCI Insight. 2020;5(5):e134172.PubMedPubMedCentralCrossRef
44.
Gómez-Piña V, Soares-Schanoski A, Rodríguez-Rojas A, del Fresno C, García F, Vallejo-Cremades MaT, et al. Metalloproteinases Shed TREM-1 ectodomain from lipopolysaccharide-stimulated human monocytes1. J Immunol. 2007;179(6):4065–73.PubMedCrossRef
45.
Gibot S, Cravoisy A, Kolopp-Sarda MN, Béné MC, Faure G, Bollaert PE, et al. Time-course of sTREM (soluble triggering receptor expressed on myeloid cells)-1, procalcitonin, and C-reactive protein plasma concentrations during sepsis. Crit Care Med. 2005;33(4):792–6.PubMedCrossRef
46.
Brenner T, Uhle F, Fleming T, Wieland M, Schmoch T, Schmitt F, et al. Soluble TREM-1 as a diagnostic and prognostic biomarker in patients with septic shock: an observational clinical study. Biomarkers. 2017;22(1):63–9.PubMedCrossRef
47.
Rogier M, Determann Julian L, Sébastien M, Gibot Johanna C, Korevaar Margreeth B, Tom V, van der Poll Christopher S, Garrard Marcus J, Schultz (2005) Serial changes in soluble triggering receptor expressed on myeloid cells in the lung during development of ventilator-associated pneumonia. Intens Care Med 31(11):1495-1500. https://​doi.​org/​10.​1007/​s00134-005-2818-7
48.
Klesney-tait J, Turnbull I, Colonna M. The TREM receptor family and signal integration. Nat Immunol. 2007;7:1266–73.CrossRef
49.
Ríos-Toro JJ, Márquez-Coello M, García-Álvarez JM, Martín-Aspas A, Rivera-Fernández R, Sáez de Benito A, et al. Soluble membrane receptors, interleukin 6, procalcitonin and C reactive protein as prognostic markers in patients with severe sepsis and septic shock. PLoS One. 2017;12(4):e0175254.PubMedPubMedCentralCrossRef
50.
Su L, Liu D, Chai W, Liu D, Long Y. Role of sTREM-1 in predicting mortality of infection: a systematic review and meta-analysis. BMJ Open. 2016;6(5): e010314.PubMedPubMedCentralCrossRef
51.
Charles PE, Noel R, Massin F, Guy J, Bollaert PE, Quenot JP, et al. Significance of soluble triggering receptor expressed on myeloid cells-1 elevation in patients admitted to the intensive care unit with sepsis. BMC Infect Dis. 2016;16(1):559.PubMedPubMedCentralCrossRef
52.
Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637–45.
53.
Neto PVdS, Carvalho JCSd, Pimentel VE, Pérez MM, Carmona-Garcia I, Neto NT, et al. Prognostic value of sTREM-1 in COVID-19 patients: a biomarker for disease severity and mortality. medRxiv. 2020:2020.09.22.20199703.
54.
da Silva-Neto PV, de Carvalho JCS, Pimentel VE, Pérez MM, Toro DM, Fraga-Silva TFC, et al. sTREM-1 Predicts Disease Severity and Mortality in COVID-19 Patients: involvement of peripheral blood leukocytes and MMP-8 Activity. Viruses. 2021;13(12):2521.PubMedPubMedCentralCrossRef
55.
Van Singer M, Brahier T, Ngai M, Wright J, Weckman AM, Erice C, et al. COVID-19 risk stratification algorithms based on sTREM-1 and IL-6 in emergency department. J Allergy Clin Immunol. 2021;147(1):99-106.e4.PubMedCrossRef
56.
de Nooijer AH, Grondman I, Lambden S, Kooistra EJ, Janssen NAF, Kox M, et al. Increased sTREM-1 plasma concentrations are associated with poor clinical outcomes in patients with COVID-19. Biosci Rep. 2021;41(7):BSR2021090.CrossRef
57.
Chen CY, Yang KY, Chen MY, Chen HY, Lin MT, Lee YC, et al. Decoy receptor 3 levels in peripheral blood predict outcomes of acute respiratory distress syndrome. Am J Respir Crit Care Med. 2009;180(8):751–60.PubMedCrossRef
58.
Lin MT, Wei YF, Ku SC, Lin CA, Ho CC, Yu CJ. Serum soluble triggering receptor expressed on myeloid cells-1 in acute respiratory distress syndrome: a prospective observational cohort study. J Formos Med Assoc. 2010;109(11):800–9.PubMedPubMedCentralCrossRef
59.
Wang YK, Tang JN, Shen YL, Hu B, Zhang CY, Li MH, et al. Prognostic utility of soluble TREM-1 in predicting mortality and cardiovascular events in patients with acute myocardial infarction. J Am Heart Assoc. 2018;7(12):e008985.PubMedPubMedCentralCrossRef
60.
Jedynak M, Siemiatkowski A, Mroczko B, Groblewska M, Milewski R, Szmitkowski M. Soluble TREM-1 serum level can early predict mortality of patients with sepsis, severe sepsis and septic shock. Arch Immunol Ther Exp (Warsz). 2018;66(4):299–306.PubMedCrossRef
61.
Jolly L, Carrasco K, Salcedo-Magguilli M, Garaud JJ, Lambden S, van der Poll T, et al. sTREM-1 is a specific biomarker of TREM-1 pathway activation. Cell Mol Immunol. 2021;18(8):2054–6.PubMedPubMedCentralCrossRef
62.
Li H, Guo S, Yan L, Meng C, Hu Y, He K, et al. Expression and purification of a functional porcine soluble triggering receptor expressed on myeloid cells 1. Anim Biotechnol. 2017;28(4):237–41.PubMedCrossRef
63.
Yang C, Chen B, Zhao J, Lin L, Han L, Pan S, et al. TREM-1 signaling promotes host defense during the early stage of infection with highly pathogenic Streptococcus suis. Infect Immun. 2015;83(8):3293–301.PubMedPubMedCentralCrossRef
64.
Yang C, Zhao J, Lin L, Pan S, Fu L, Han L, et al. Targeting TREM-1 signaling in the presence of antibiotics is effective against streptococcal toxic-shock-like syndrome (STSLS) caused by streptococcus suis. Front Cell Infect Microbiol. 2015;5:79.PubMedPubMedCentralCrossRef
65.
66.
Derive M, Boufenzer A, Bouazza Y, Groubatch F, Alauzet C, Barraud D, et al. Effects of a TREM-like transcript 1–derived peptide during hypodynamic septic shock in pigs. Shock. 2013;39(2):176–82.PubMedCrossRef
67.
Derive M, Boufenzer A, Gibot S. Attenuation of responses to endotoxin by the triggering receptor expressed on myeloid cells-1 inhibitor LR12 in nonhuman primate. Anesthesiology. 2014;120(4):935–42.PubMedCrossRef
68.
Boufenzer A, Lemarié J, Simon T, Derive M, Bouazza Y, Tran N, et al. TREM-1 mediates inflammatory injury and cardiac remodeling following myocardial infarction. Circ Res. 2015;116(11):1772–82.PubMedCrossRef
69.
Horst SA, Linnér A, Beineke A, Lehne S, Höltje C, Hecht A, et al. Prognostic value and therapeutic potential of TREM-1 in Streptococcus pyogenes- induced sepsis. J Innate Immun. 2013;5(6):581–90.PubMedPubMedCentralCrossRef
70.
Gibot S, Buonsanti C, Massin F, Romano M, Kolopp-Sarda MN, Benigni F, et al. Modulation of the triggering receptor expressed on the myeloid cell type 1 pathway in murine septic shock. Infect Immun. 2006;74(5):2823–30.PubMedPubMedCentralCrossRef
71.
Qian L, Weng XW, Chen W, Sun CH, Wu J. TREM-1 as a potential therapeutic target in neonatal sepsis. Int J Clin Exp Med. 2014;7(7):1650–8.PubMedPubMedCentral
72.
Wang F, Liu S, Wu S, Zhu Q, Ou G, Liu C, et al. Blocking TREM-1 signaling prolongs survival of mice with Pseudomonas aeruginosa induced sepsis. Cell Immunol. 2012;272(2):251–8.PubMedCrossRef
73.
Sharapova TN, Romanova EA, Chernov AS, Minakov AN, Kazakov VA, Kudriaeva AA, et al. Protein PGLYRP1/Tag7 peptides decrease the proinflammatory response in human blood cells and mouse model of diffuse alveolar damage of lung through blockage of the TREM-1 and TNFR1 receptors. Int J Mol Sci. 2021;22(20):11213.PubMedPubMedCentralCrossRef
74.
75.
Sigalov AB. A novel ligand-independent peptide inhibitor of TREM-1 suppresses tumor growth in human lung cancer xenografts and prolongs survival of mice with lipopolysaccharide-induced septic shock. Int Immunopharmacol. 2014;21(1):208–19.PubMedPubMedCentralCrossRef
76.
Gibot S, Jolly L, Lemarié J, Carrasco K, Derive M, Boufenzer A. Triggering receptor expressed on myeloid cells-1 inhibitor targeted to endothelium decreases cell activation. Front Immunol. 2019;10:2314.PubMedPubMedCentralCrossRef
77.
Gattis JL, Washington AV, Chisholm MM, Quigley L, Szyk A, McVicar DW, 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. 2006;281(19):13396–403.PubMedCrossRef
78.
Cuvier V, Lorch U, Witte S, Olivier A, Gibot S, Delor I, et al. A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition. Br J Clin Pharmacol. 2018;84(10):2270–9.PubMedPubMedCentralCrossRef
79.
Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200–11.PubMedPubMedCentralCrossRef
80.
81.
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486–552.PubMedCrossRef
82.
François B, Lambden S, Garaud JJ, Derive M, Grouin JM, Asfar P, et al. Evaluation of the efficacy and safety of TREM-1 inhibition with nangibotide in patients with COVID-19 receiving respiratory support: the ESSENTIAL randomised, double-blind trial. EClinicalMedicine. 2023;60: 102013.PubMedPubMedCentralCrossRef
83.
84.
85.
Yoo H, Im Y, Ko R-E, Lee JY, Park J, Jeon K. Association of plasma level of high-mobility group box-1 with necroptosis and sepsis outcomes. Sci Rep. 2021;11(1):9512.PubMedPubMedCentralCrossRef
86.
Delogu G, Lo Bosco L, Marandola M, Famularo G, Lenti L, Ippoliti F, et al. Heat shock protein (HSP70) expression in septic patients. J Crit Care. 1997;12(4):188–92.PubMedCrossRef
Metadata
Title
Triggering receptor expressed on myeloid cells-1 in sepsis, and current insights into clinical studies
Authors
Vivienne Theobald
Felix Carl Fabian Schmitt
Chiara Simone Middel
Lena Gaissmaier
Thorsten Brenner
Markus Alexander Weigand
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2024
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-024-04798-2

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