TREM-1 (Triggering Receptor Expressed on Myeloid Cells): A New Player in Acute Inflammatory Responses
- 1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
- 2Department of Pathology, University of Brescia, Brescia, Italy
- Reprints or correspondence: Dr. Marco Colonna, Dept. of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid St., St. Louis, MO 63110 (mcolonna{at}pathology.wustl.edu).
Abstract
TREM-1 (triggering receptor expressed on myeloid cells), a recently discovered receptor of the immunoglobulin superfamily, activates neutrophils and monocytes/macrophages by signaling through the adapter protein DAP12. TREM-1 is the best-characterized member of a growing family of DAP12-associated receptors that regulate the function of myeloid cells in innate and adaptive responses. TREM-1 amplifies Toll-like receptor—initiatedresponses against microbial challenges and potentiates the secretion of proinflammatory chemokines and cytokines in response to bacterial and fungal infections. Blockade of TREM-1 reduces inflammation and increases survival in animal models of bacterial infections that cause systemic hyperinflammatory syndromes. The TREM-1 ligands are not known. Characterization of TREM-1 natural ligands will further illuminate the mechanisms regulating innate responses against pathogens. Whatever the ligands, targeted activation or blockade of TREM-1 and its ligands may help maximize the efficacy of existing treatments for sepsis.
Innate responses against infections provide a first line of host defense that occurs rapidly, is aimed at a wide range of pathogens, and involves the coordinate action of several cells types and serum proteins [1]. The major innate effector cells include professional phagocytes (neutrophils and monocytes/macrophages) and natural killer (NK) cells. These cells display a variety of cell surface receptors that recognize either pathogens or endogenous molecules that are expressed during tissue damage. The Toll-like receptors (TLRs) directly recognize molecular patterns common to many pathogens, such as lipopolysaccharide (LPS) [2–5]. Different types of G protein—linked 7-transmembrane domain receptors trigger inflammatory responses upon recognition of bacterial peptides (e.g., FMLP [N-formyl-methionylleucyl-phenylalanine]), lipid mediators, complement factors, or proinflammatory chemokines [6–8]. The mannose and scavenger receptors bind microbes and foreign particles, either directly or through the mannose-binding lectin, allowing for phagocytosis [9–11]. After the onset of adaptive responses, the Fc and complement receptors also mediate phagocytosis of infectious agents coated with immunoglobulins and complement fragment C3b, respectively [9].
There is evidence that phagocyte and NK cell—mediated responses are also controlled by several families of receptors that are characterized by the presence of both inhibitory and activating isoforms [12, 13]. Inhibitory receptors recognize endogenous “self” molecules (e.g., major histocompatibility complex class I or CD47) and thereby mediate tolerance. Some activating receptors recognize pathogen-encoded molecules, which are homologous to host endogenous molecules and probably have evolved in an attempt by pathogens to engage inhibitory receptors and escape surveillance [14, 15]. Other activating receptors recognize endogenous molecules that are expressed at high levels, primarily in infected cells [16–19].
Inhibitory isoforms contain cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which allow for recruitment of protein tyrosine phosphatases that mediate inhibitory signals [20]. In contrast, activating isoforms are truncated in their cytoplasmic tails and deliver stimulatory signals by associating with transmembrane adapter proteins, such as CD3 γ, the γ chain of Fc receptors, and DAP12/KARAP [20]. All of these adapters contain immunoreceptor tyrosinebased activation motifs (ITAMs), which recruit protein tyrosine kinases that mediate activation. The balance between activating and inhibitory signals generated by the engagement of these receptors ultimately controls neutrophil- and macrophage-mediated phagocytosis, respiratory burst, and release of proinflammatory cytokines, as well as NK cell release of cytotoxic granules and interferon-γ.
Trem-1 (Triggering Receptor Expressed on Myeloid Cells) Is a Dap12-Associated Receptor That Activates Neutrophils and Monocytes/Macrophages
Many activating NK cell receptors associate with the transmembrane adapter DAP12 [12]. However, DAP12 is expressed in NK cells and in other leukocytes, indicating that this adapter transduces ITAM-mediated activation signals for a number of receptors in other cell types. To identify such receptors in effector cells of innate responses, we searched expressed sequence tag (EST) databases for protein sequences similar to DAP12-associated NK cell receptors. By using this approach, we identified several novel receptors, one of which, TREM-1, is selectively expressed in neutrophils and monocytes/macrophages [21].
Human TREM-1 is a 30-kDa glycoprotein of the immunoglobulin superfamily. It consists of a single extracellular immunoglobulin-like domain of the V-type, a transmembrane region with a charged residue, lysine, and a short cytoplasmic tail (figure 1). It shares homology with the NK cell receptor NKp44 [22], the leukocyte receptor CMRF-35 [23], and the polyimmunoglobulin receptor [24]. TREM-1 is expressed at late stages of myeloid cell differentiation [25] and associates with DAP12 for signaling and function [21]. Activation of the TREM-1/DAP12 signaling pathway promotes recruitment and activation of protein tyrosine kinases, leading to tyrosine phosphorylation of many protein species, Ca2+ mobilization, activation of extracellular signal—regulated kinases (ERK), and transcription complexes downstream of ERK [21, 26].
Figure 1.
Schematic representation of TREM-1 (triggering receptor expressed on myeloid cells)/DAP12 complex. TREM-1 engagement leads to phosphorylation of DAP12 immunoreceptor tyrosine-based activation motifs and binding of the Src homology 2 (SH2) domains of a protein tyrosine kinase (e.g., Syk), which mediates activation. ITAM, immunoreceptor tyrosine-based activation motifs.
Function of Trem-1 in Acute Inflammation
By using a specific monoclonal antibody (MAb), we showed that human TREM-1 is expressed on blood neutrophils and on CD14high monocytes/macrophages [21]. In addition, in normal tissues, TREM-1 is selectively expressed in lung alveolar macrophages (figure 2), which specialize in the clearance of pathogens, apoptotic cells, and macromolecules. This cellular and tissue distribution suggested that a role exists for TREM-1 in inflammatory responses against infections. Indeed, TREM-1 is strongly expressed in infections of human skin and lymph nodes caused by gram-positive and -negative bacteria and fungi (figure 3) [27]. In these lesions, TREM-1 is expressed in not only neutrophilic infiltrates but also the epithelioid cells of monocytic origin surrounding granulomatous reactions. Conversely, TREM-1 is poorly expressed or not expressed in granulomatous infections caused by Mycobacterium tuberculosis or in foreign body granulomas (figure 3).
Figure 2.
Expression of TREM-1 (triggering receptor expressed on myeloid cells) in human alveolar macrophages. Human lung section shows clustered and single alveolar macrophages strongly stained with anti—TREM-1 monoclonal antibody. TREM-1 was detected by the indirect immunoperoxidase method, which uses ethyl-carbazole as chromogen and Meyer's hematoxylin for nuclear counterstain.
Figure 3.
TREM-1 (triggering receptor expressed on myeloid cells) is expressed in acute bacterial and fungal infections such as a granuloma caused by Aspergillus fumigatus (A). In contrast, TREM-1 is poorly expressed in a lymph node granuloma caused by Mycobacterium tuberculosis (B) and virtually undetectable in a lymph node granuloma caused by sarcoidosis (C) or in a foreign body granuloma induced by vascular prosthesis (D). In panel D, the prosthetic material is visible in the upper half of the section above the foreign body giant cell reaction. TREM-1 was detected by the indirect immunoperoxidase method, which uses ethyl-carbazole as chromogen and Meyer's hematoxylin for nuclear counterstain.
It remains unclear whether TREM-1 directly recognizes bacterial products similar to TLRs. Recent work with leprosy indicates that expression of TREM-1 correlates more with inflammatory response than with bacterial proliferation (R. Modlin, personal communication). Therefore, it is more likely that TREM-1 recognizes a soluble protein or a cell-surface protein that is expressed ex novo or overexpressed as a result of inflammation and/or tissue damage.
Regardless of the nature of TREM-1 ligand, engagement of TREM-1 on neutrophils and monocytes results in initiation and amplification of inflammatory responses. Ligation of TREM-1 with a MAb stimulates production of the proinflammatory chemokines interleukin (IL)—8, monocyte chemoattractant protein (MCP)—1, MCP-3, and macrophage inflammatory protein—1α [21]. TREM-1 triggering also induces secretion of tumor necrosis factor (TNF)—α and IL-1β, especially when LPS is used as a costimulus, demonstrating the ability of TREM-1 to amplify proinflammatory responses induced by TLR [21]. In addition, LPS and other TLR ligands up-regulate TREM-1 expression. Thus, TREM-1 and TLR cooperate to produce an inflammatory response burst.
The role of TREM-1 as an amplifier of inflammation has been confirmed in vivo in animal models of acute bacterial inflammation (e.g., LPS-induced shock, intraperitoneal injection of live Escherichia coli, and cecal ligation and puncture) [27]. In all these models, blocking TREM-1 signaling with a soluble TREM-1—IgG fusion protein reduces hyperinflammatory responses and death. Conversely, DAP12-transgenic mice, in which the TREM-1/DAP12-dependent pathway is constitutively active independent of the engagement of TREM-1, are highly susceptible to LPS-induced shock [28]. In addition, mice overexpressing DAP12 develop pneumonia due to massive macrophage infiltration in the lung [28]. Together, these results demonstrate a crucial role of TREM-1 in the initiation and amplification of inflammatory responses. They also implicate TREM-1 as a potential therapeutic target in diseases characterized by an excessive inflammatory response to infections, such as septic shock and acute lung injury (ALI).
Septic shock results from a systemic response to infections that is characterized by increased systemic levels of proinflammatory mediators (e.g., TNF-α, IL-1β high mobility group [HMG]—1 protein, and macrophage migration inhibitory factor) [29, 30]. ALI is caused by a lung accumulation of neutrophils, which leads to massive release of proinflammatory cytokines, loss of epithelial and endothelial integrity, and development of interstitial pulmonary edema [31]. Strategies for the treatment of septic shock and ALI have been based on blocking or attenuating TNF-α and IL-1 activity [32, 33]. Modulation of TREM-1 signaling may further assist the outcome in patients with sepsis and ALI.
The Trem Locus: An Extended Family of Activating and Inhibitory Receptors Regulating Innate and Adaptive Responses
Alignment of the human TREM-1 cDNA with genomic sequence database releases of the public human genome projects reveals that the TREM-1 gene is located on human chromosome 6p21. The TREM locus is located within a gene cluster that includes also the NKp44 gene (Ly95) and the TREM-2 gene. TREM-2 is a DAP12-associated receptor structurally related to TREM-1, which is expressed on monocyte-derived dendritic cells (DCs) and promotes their activation in vitro [34]. Thus, TREM-2 may regulate DC function in adaptive responses in vivo. In addition, recent evidence demonstrates that a rare genetically inherited deficit of TREM-2 leads to a severe disease characterized by presenile dementia and bone cysts [35]. Thus, TREM-2 may also regulate the function of myeloid cell types in the brain and bones (e.g., microglial cells and osteoclasts).
TREM-1 is highly conserved in mice and encoded in a syntenic region of chromosome 17. The mouse TREM cluster includes TREM-1 and TREM-2 loci and an additional TREM-3 gene, which encodes for a receptor that activates macrophage cell lines [36, 37]. In humans, the TREM-3 region contains only 1 exon; no full-length cDNA has been identified. Both the human and mouse TREM gene clusters includes 1 other gene encoding a TREM-related molecule. This contains an ITIM motif in the cytoplasmic tail and may, therefore, function as an inhibitory receptor [38]. In addition, 3 TREM-like immunoglobulin domains can be predicted by computational analysis of the human and mouse TREM region. However, the corresponding cDNAs have not yet been cloned. Thus, the TREM gene cluster includes several genes that encode both activating and inhibitory receptors, as do other immune gene clusters.
In conclusion, TREMs are emerging as a new extended family of related receptors that include both activating and inhibitory isoforms and regulate both innate and adaptive immune responses mediated by myeloid cells. It will be important to investigate the genetics of this locus in humans (i.e., the variability in gene numbers and the polymorphism of each gene). If the TREM gene cluster has evolved under the selective pressure for resistance to pathogen infection, one would expect a considerable plasticity of this cluster [13]. Although TREM-1 is mostly implicated in innate responses, other TREMs may control functions of myeloid cells, which are implicated in T cell stimulation and brain and bone homeostasis. The identification of TREM ligands will be crucial to understand their immune and nonimmune functions.
- © 2003 by the Infectious Diseases Society of America
References
This Article
- AbstractFree
- » Full Text (HTML)Free
- Full Text (PDF)Free
Classifications
-
- New Mediators of Sepsis
Services
Citing Articles
Google Scholar
PubMed
Related Content
Share
- Email this article
-
CiteULike
Connotea
Delicious
Facebook
Google+
Mendeley
Twitter
Published on behalf of
IDSA Members: For your free access to this journal, log in via the IDSA members area.
The Journal
Impact Factor: 6.288
5-Yr impact factor: 6.103
For The Media
For Authors
- Services for authors
- Self-archiving policy
- IDSA Conflict of Interest policy
- Instructions for Authors
- ICMJE Form
- Submit Now!
Open access options for authors visit Oxford Open
This journal enables compliance with the NIH Public Access Policy
Corporate Services
Alerting Services
Related IDSA Publications
