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