The characteristics and pivotal roles of triggering receptor expressed on myeloid cells-1 in autoimmune diseases

doi:10.1016/j.autrev.2018.07.008

Autoimmunity Reviews

Volume 18, Issue 1, January 2019, Pages 25-35

https://doi.org/10.1016/j.autrev.2018.07.008 Get rights and content

Highlights

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TREM-1 engagement directly induces or amplifies inflammatory responses.
•
TREM-1 expression was dysregulated in inflammatory autoimmune diseases.
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TREM-1 may serve as a promising therapeutic target for autoimmune disease.

Abstract

Triggering receptor expressed on myeloid cells-1 (TREM-1) engagement can directly trigger inflammation or amplify an inflammatory response by synergizing with TLRs or NLRs. Autoimmune diseases are a family of chronic systemic inflammatory disorders. The pivotal role of TREM-1 in inflammation makes it important to explore its immunological effects in autoimmune diseases. In this review, we summarize the structural and functional characteristics of TREM-1. Particularly, we discuss recent findings on TREM-1 pathway regulation in various autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), type 1 diabetes (T1D), and psoriasis. This receptor may potentially be manipulated to alter the inflammatory response to chronic inflammation and possible therapies are explored in this review.

Introduction

Autoimmune diseases are a family of chronic systemic inflammatory disorders, characterized by the dysregulation of the immune system which finally results in the break of tolerance to self-antigen. Fine-tuning the immune response is absolutely critical to prevent excessive inflammation and tissue damage in autoimmune diseases. Complex overlapping pathogenic pathways span multiple aspects of the immune system. A better understanding of these pathways has led to the development of pharmacologic therapies targeting specific elements of the immune system which play a role in disease pathogenesis.

Triggering receptor expressed on myeloid cells (TREMs) are a family of cell surface receptors that play important roles in innate and adaptive immunity. In a number of chronic inflammatory conditions and malignancies, TREMs has been implicated in disease severity and progression. Among them, TREM-1 (CD354) was the first identified. TREM-1 is a pivotal innate immune receptor, which acts to initiate inflammation or to amplify inflammatory responses by cross-talking with Toll like receptors (TLRs) and/or nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). It was initially demonstrated that TREM-1 was predominantly associated with infectious diseases [1,2]. Indeed, TREM-1 receptor and its signaling pathways contribute to the pathology of several non-infectious acute and chronic inflammatory diseases.

Given the role that TREM-1 plays in the numerous inflammatory conditions, a large bulk of pre-existing data clearly identifies a key functional role for TREM-1 in numerous types of autoimmune diseases, including rheumatoid arthritis (RA) [3,4], systemic lupus erythematosus (SLE) [[5], [6], [7]], inflammatory bowel diseases (IBD) [8,9], type 1 diabetes (T1D) [10], and psoriasis [11]. Blockade of TREM-1 could be a novel therapeutic target in autoimmune diseases without impairing the host defense against microbes. The aim of this review was to discuss the state of the field of TREM-1 biology, including the structure and expression pattern of TREM-1, the putative ligands for TREM-1, TREM-1 signaling pathway and soluble TREM-1 (sTREM-1), etc. Furthermore, the strategy for TREM-1 blockade is also reviewed in context of developing novel therapeutics. Particular emphasis is placed on role of TREM-1 in autoimmune diseases and the challenges that remain in the treatment of autoimmune diseases up to date.

Section snippets

Structure and expression pattern of TREM-1

The gene encoding TREM-1 is mapped to human chromosome 6p21. TREM-1 is a 30 kD immunoglobulin superfamily member. Crystal structure data are inconclusive as to whether or not TREM-1 forms homodimers [12,13]. Human membrane TREM-1 is a 234 amino acid type I transmembrane protein consisting of a single extracellular immunoglobulin (Ig)-like domain (184 amino acids), a transmembrane region with a positively charged lysine residue, and a short cytoplasmic tail (5 amino acids) lacking any signaling

RA

Rheumatoid arthritis is a systemic autoimmune disease caused by various factors, and is characterized by chronic inflammation of synovial joints, which leads to progressive destruction of cartilage and bone causing damage to extra-articular tissue [97]. Overproduction of pro-inflammatory cytokines and chemokines are strongly associated with the pathology of RA [98]. Although TNF inhibitors have been widely used in the treatment of RA, substantial proportion (up to a third) of RA patients

TREM-1 Blockade: a novel therapeutic approach

Enhanced TREM-1 expression and activation were observed in several infectious and noninfectious inflammatory disorders, suggesting a pathogenetic role for this molecule. Several preclinical approaches have been developed for TREM-1 blockade, from genetic invalidation to the use of antibodies or decoy receptors, with the purpose of either identification of TREM-1 involvement in pathologies or treatment. A number of strategies have been developed to inhibit TREM-1 receptor activation using small

Conclusion and clinical perspectives

Accumulating data suggest that TREM-1 is commonly referred to as amplifier of inflammatory immune responses in the context with PRRs. Moreover, engagement of TREM-1 by itself can also lead to myeloid cell activation including the production of inflammatory cytokines and chemokines, and phagocytosis. A thorough characterization of TREM-1 will allow for a better understand of the role TREM-1 in autoimmune disorders associated with exaggerated inflammation (e.g., RA, SLE, IBD, etc.) and may

Disclosures

The authors declare no financial or commercial conflict of interest.

Acknowledgements

This study was supported by the Natural Science Foundation of Zhejiang Province (grant number LQ16C080002), the Research Development Foundation of Wenzhou Medical University (grant number QTJ14025), and the Science and Technology Plan Project of Wenzhou (grant number Y20160179, Y20160191).

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Inflammation is an important part of the wound healing process. The stress hormone epinephrine has been demonstrated to modulate the inflammatory response via its interaction with β2-adrenergic receptor (β2-AR). However, the precise molecular mechanism through which β2-AR exerts its influence on inflammation during the wound healing process remains an unresolved question.
Transcriptome datasets of wound and macrophages from the GEO database were reanalyzed using bioinformatics. The role of β2-AR in wound healing was explored by a mouse hind paw plantar wound model, and histological analyses were performed to assess wound healing. In vivo and in vitro assays were performed to elucidate the role of β2-AR on the inflammatory response. Triggering receptor expressed on myeloid cells 1 (Trem1) was knocked down with siRNA on RAW cells and western blot and qPCR assays were performed.
Trem1 was upregulated within 24 h of wounding, and macrophage β2-AR activation also upregulated Trem1. In vivo experiments demonstrated that β2-AR agonists impaired wound healing, accompanied by upregulation of Trem1 and activation of cAMP/PKA/CREB pathway, as well as by a high level of pro-inflammatory cytokine production. In vitro experiments showed that macrophage β2-AR activation amplified LPS-induced inflammation, and knockdown of Trem1 reversed this effect. Using activator and inhibitor of cAMP, macrophage β2-AR activation was confirmed to upregulate Trem1 via the cAMP/PKA/CREB pathway.
Our study found that β2-AR agonists increase Trem1 expression in wounds, accompanied by amplification of the inflammatory response, impairing wound healing. β2-AR activation in RAW cells induces Trem1 upregulation via the cAMP/PKA/CREB pathway and amplifies LPS-induced inflammatory responses.
Soluble triggering receptor expressed on myeloid cell-1 reflects the cross-sectional activity of microscopic polyangiitis and granulomatosis with polyangiitis
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We investigated whether soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) reflects cross-sectional activity of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA).
Forty-seven MPA and 32 GPA patients with well-documented clinical records and stored sera were enrolled. sTREM-1 levels were evaluated using Magnetic Luminex® assay, and disease activity was assessed using Birmingham vasculitis activity score (BVAS). Patients were divided into two groups according to the upper and lower halves of BVAS. Receiver operator characteristic (ROC) curve analysis was used to identify cut-off for determining upper half of BVAS. Linear and binary logistic regression was performed to evaluate the association between sTREM-1 and disease activity and status.
The median age of patients was 67.0 years, and 58.2 % were women. The median BVAS and sTREM-1 were 12.0 and 467.1 pg/mL. sTREM-1 was significantly correlated with BVAS along with five-factor score, Short-Form 36-Item Health Surveys, and C-reactive protein. In multivariable linear regression analysis, erythrocyte sedimentation rate (standardised β 0.241), and sTREM-1 (standardised β 0.288) were correlated with BVAS. ROC analysis revealed that the cut-off of sTREM-1 for the upper half of BVAS was 474.1 pg/mL. MPA and GPA patients with sTREM-1 ≥474.1 pg/mL exhibited a significantly higher risk for the upper half of BVAS than those without (relative risk 5.932). Multivariable logistic regression analysis demonstrated sTREM-1 ≥474.1 pg/mL (odds ratio 5.662) was associated with the upper half of BVAS.
sTREM-1 reflects the activity of MPA and GPA, suggesting its role as a potential biomarker for assessing disease severity.
TREM-1 exacerbates bleomycin-induced pulmonary fibrosis by aggravating alveolar epithelial cell senescence in mice
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Citation Excerpt :
It has been well documented that TREM-1 mainly expresses on myeloid cells and plays a pivotal role in inflammation amplification, synergism with Toll-like receptors and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) signaling [16,17]. We have reported that the blockade of TREM-1 with an inhibitory peptide attenuates lipopolysaccharide-induced acute lung injury [16,17]. However, recent literature investigates whether TREM-1 is involved in fibrotic diseases.
Our previous study showed that triggering receptors expressed on myeloid cell-1 (TREM-1) was upregulated in bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model. However, the role of TREM-1 in the development of PF and its underlying mechanism remain unclear. Herein, we report that the prophylactical blockade of TREM-1 using a decoy peptide dodecapeptide (LR12) exerted protective effects against BLM-induced PF in mice, with a higher survival rate, attenuated tissue injury, and less extracellular matrix deposition. Interestingly, therapeutic blockade of TREM-1 at the early stage of fibrosis also attenuated BLM-induced PF, suggesting a non-inflammatory effect. More importantly, we observed that TREM-1 blockade with LR12 significantly reduced the expression of the senescence-relative protein, including p16, p21, p53, and γ-H2AX in the lungs of PF mice. Notably, TREM-1 was upregulated in alveolar epithelial cells (AECs) and correlated with the levels of senescence markers in BLM-treated mice. In vitro, activating TREM-1 with an agonistic antibody exacerbated BLM-induced senescence in MLE12 cells, a murine AEC cell line. Furthermore, prophylactic or therapeutic blockade of TREM-1 protected MLE12 cells from senescence induced by BLM or H₂O₂. In conclusion, our findings elucidate a pro-fibrotic effect of TREM-1 by inducing AECs senescence in PF, providing a potential strategy for fibrotic disease treatment.
IL-23 production in human macrophages is regulated negatively by tumor necrosis factor α-induced protein 3 and positively by specificity protein 1 after stimulation of the toll-like receptor 7/8 signaling pathway
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Citation Excerpt :
In our study, resiquimod was found to enhance Sp1 expression via the TLR7/8 signaling pathway. TREM-1 amplifies an inflammatory response in synergy with not only TLR4-signaling, but also TLR7/8-signaling [58, 59, 60], and we found that siRNA for TREM-1 reduced Sp1 levels after exposure to resiquimod. IL-23 production in human macrophages is negatively regulated by TNFAIP3.
The IL-23/IL-17 axis plays an important role in the development of autoimmune diseases, but the mechanism regulating IL-23 production is mainly unknown. We investigated how TNFAIP3 and Sp1 affect IL-23 production by human macrophages after exposure to resiquimod, a TLR7/8 agonist.
IL-23 production was significantly upregulated by resiquimod but only slightly by LPS (a TLR4 agonist). Interestingly, IL-23 levels were significantly attenuated after sequential stimulation with LPS and resiquimod, but IL-12p40 and IL-18 levels were not. TLR4-related factors induced by LPS may regulate IL-23 expression via TLR7/8 signaling. LPS significantly enhanced TNFAIP3 and IRAK-M levels but reduced Sp1 levels. After exposure to resiquimod, RNA interference of TNFAIP3 upregulated IL-23 significantly more than siRNA transfection of IRAK-M did. In contrast, knockdown of Sp1 by RNA interference significantly attenuated IL-23 production. Transfection with siRNA for TNFAIP3 enhanced IL-23 expression significantly. After stimulation with resiquimod, GW7647—an agonist for PPARα (an inducer of NADHP oxidase)—and siRNA for UCP2 (a negative regulator of mitochondrial ROS generation) enhanced TNFAIP3 and reduced IL-23. siRNA for p22phox and gp91phox slightly increased Sp1 levels. However, after exposure to resiquimod siRNA-mediated knockout of DUOX1/2 significantly enhanced Sp1 and IL-23 levels, and decreased TNFα-dependent COX-2 expression. Concomitantly, TNFAIP3 levels was attenuated by DUOX1/2 siRNA. TNFAIP3 and Sp1 levels are reciprocally regulated through ROS generation.
In conclusion, after stimulation of the TLR7/8 signaling pathway IL-23 production in human macrophages is regulated negatively by TNFAIP3.
Soluble triggering receptor expressed on myeloid cells-1 as a serum biomarker of early neurologic deterioration and prognosis in acute supratentorial intracerebral hemorrhage
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Citation Excerpt :
Besides National Institutes of Health Stroke Scale (NIHSS) score and hematoma volume, some other biomarkers have been recently investigated for assessing their associations with END and prognosis of ICH [4]. Triggering receptor expressed on myeloid cells-1 (TREM-1), a transmembrane immune receptor, is primarily expressed on the surface of phagocytic cells, functioning as a potent amplifier of inflammation [5]. Intriguingly, TREM-1 can be expressed in brain tissues, especially in microglial cells, and its expression is greatly up-regulated after acute brain injury [6].
Triggering receptor expressed on myeloid cells-1 (TREM-1) participates in neuroinflammation. We intended to ascertain whether serum soluble TREM-1 (sTREM-1) could be utilized as a biomarker of inflammation, severity, early neurologic deterioration (END) and outcome after primary intracerebral hemorrhage (ICH).
Serum sTREM-1 levels were gauged in 104 ICH patients and 104 healthy controls. END was diagnosed when the National Institutes of Health Stroke Scale (NIHSS) score increased ≥ 4 points or death between admission and 24 h after admission. Patients with a modified Rankin scale score of > 2 at 3 months were considered to have poor outcome.
As compared to controls, patients exhibited significantly elevated serum sTREM-1 levels (median: 309.0 vs 67.9 pg/ml). Serum sTREM-1 concentrations were intimately correlated with NIHSS score (r = 0.574), hematoma volume (r = 0.554), blood leukocyte count (r = 0.529) and serum C-reactive protein concentrations (r = 0.509). Serum sTREM-1 concentrations > 309.0 pg/ml independently predicted END and poor outcome with odds ratio values of 4.054 and 4.721 respectively. Serum sTREM-1 concentrations distinguished END and poor outcome with areas under receiver operating characteristic curve of 0.789 and 0.813 respectively.
Serum sTREM-1 may represent a promising inflammatory biomarker for assessment of severity and prediction of END and poor outcome after ICH.

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The characteristics and pivotal roles of triggering receptor expressed on myeloid cells-1 in autoimmune diseases

Highlights

Abstract

Introduction

Section snippets

Structure and expression pattern of TREM-1

RA

TREM-1 Blockade: a novel therapeutic approach

Conclusion and clinical perspectives

Disclosures

Acknowledgements

Curr Opin Immunol

Med Hypotheses

J Invest Dermatol

J Mol Biol.

Structure

Immunobiology

Exp Mol Pathol

Cytokine

J Crit Care

Int Immunopharmacol

Exp Cell Res

Life Sci

Immunol Lett

Blood

Biochem Biophys Res Commun

Blood

J Autoimmun.

Curr Opin Immunol

Immunol Lett

Dev Comp Immunol.

Cell Host Microbe

J Biol Chem

J Biol Chem

Int Immunopharmacol

Immunol Lett

Mol Immunol

Lancet

Autoimmun Rev

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

Nature

TREM-1 expression is increased in the synovium of rheumatoid arthritis patients and induces the expression of pro-inflammatory cytokines

Rheumatology (Oxford)

Serum levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and pentraxin 3 (PTX3) as markers of infection in febrile patients with systemic lupus erythematosus

Clin Exp Rheumatol

Serum soluble triggering receptor on myeloid cells-1 (sTREM-1) is elevated in systemic lupus erythematosus but does not distinguish between lupus alone and concurrent infection

Inflammation

Clinical association of a soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in patients with systemic lupus erythematosus

Immunol Invest

TREM-1--expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases

J Clin Invest

An antibody against triggering receptor expressed on myeloid cells 1 (TREM-1) dampens proinflammatory cytokine secretion by lamina propria cells from patients with IBD

Inflamm Bowel Dis

Levels of soluble TREM-1 in children with newly diagnosed type 1 diabetes and their siblings without type 1 diabetes: a Danish case-control study

Pediatr Diabetes

TREMs in the immune system and beyond

Nat. Rev. Immunol.

TREM-1 multimerization is essential for its activation on monocytes and neutrophils

Cell Mol Immunol

TREM-1: intracellular signaling pathways and interaction with pattern recognition receptors

J Leukoc Biol

The TREM receptor family and signal integration

Nat Immunol

Induction of triggering receptor expressed on myeloid cells (TREM-1) in airway epithelial cells by 1,25(OH)(2) vitamin D(3)

Innate Immun

Elevated synovial expression of triggering receptor expressed on myeloid cells 1 in patients with septic arthritis or rheumatoid arthritis

Ann Rheum Dis

Soluble triggering receptor expressed on myeloid cells and the diagnosis of pneumonia

N Engl J Med

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

Lipopolysaccharide-induced up-regulation of triggering receptor expressed on myeloid cells-1 expression on macrophages is regulated by endogenous prostaglandin E2

J Immunol

Cathelicidin peptide LL-37 modulates TREM-1 expression and inflammatory responses to microbial compounds

Inflammation

TREM-1 expression in macrophages is regulated at transcriptional level by NF-kappaB and PU.1

Eur J Immunol.

CD44 antibodies and immune thrombocytopenia in the amelioration of murine inflammatory arthritis

PLoS One

A polymorphism in the human serotonin 5-HT2A receptor gene may protect against systemic sclerosis by reducing platelet aggregation