TREM2-Ligand Interactions in Health and Disease

Abstract

The protein Triggering receptor expressed on myeloid cells-2 (TREM2) is an immunomodulatory receptor with a central role in myeloid cell activation and survival. In recent years, the importance of TREM2 has been highlighted by the identification of coding variants that increase risk for Alzheimer’s disease and other neurodegenerative diseases. Animal studies have further shown the importance of TREM2 in neurodegenerative and other inflammatory disease models including chronic obstructive pulmonary disease, multiple sclerosis, and stroke. A mechanistic understanding of TREM2 function remains elusive, however, due in part to the absence of conclusive information regarding the identity of endogenous TREM2 ligands. While many TREM2 ligands have been proposed, their physiological role and mechanism of engagement remain to be determined. In this review, we highlight the suggested roles of TREM2 in these diseases, recent advances in our understanding of TREM2, and discuss putative TREM2-ligand interactions and their potential roles in signaling during health and disease. We develop a model based on the TREM2 structure to explain how different TREM2 ligands might interact with the receptor and how disease-risk variants may alter ligand interactions. Finally, we propose future experimental directions to establish the role and importance of these different interactions on TREM2 function.

Microglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets

“…Expression of TREM2 was noted at the time to be present on macrophages and dendritic cells but not monocytes or granulocytes (Bouchon, Dietrich, & Colonna, ). In the brain, TREM2 is expressed in microglia and perivascular macrophages but not in neurons and other brain cell types (Kober & Brett, ). Protein expression of TREM2 is low in resting microglia but is highly up‐regulated in microglia surrounding amyloid plaques in AD brains and also appears to be high in infiltrating macrophages at early cerebral infarcts (Fahrenhold et al, ; Lue et al, ).…”

Role of triggering receptor expressed on myeloid cells 2 in neuroinflammation and neurodegeneration of the central nervous system

“…As a most prevalent explanation of this multifaceted TREM2 signaling, a model of activating versus tonic receptor engagement by multivalent, high‐affinity versus monovalent, low‐affinity ligands is considered (Fig. ) …”

“…In 2003, Gram‐positive and Gram‐negative bacteria, such as Escherichia coli , Staphylococcus aureus , Proteus mirabilis and Streptococcus pyogenes ; fungus, such as Candida guilliermondii ; and an astrocytoma cell line, as well as polyanionic molecules, were identified as TREM2 ligands . Furthermore, it has been reported that TREM2 can bind to various cells and cell‐derived molecules, such as apoptotic neuronal cells; anionic molecules derived from apoptotic cells, such as phosphatidylethanolamine, phosphatidylserine (PS) and cardiolipin; heat shock protein 60; and apolipoprotein (Apo) including ApoE . Among the various identified TREM2 ligands, the affinity between TREM2 and phosphatidylserine is very high, whereas the affinity between TREM2 and heat shock protein 60 is very low (Fig.…”

A Novel TREM2-Mediated Link between Diabetes and Cognitive Impairment: Recent Findings and Future Perspectives

“…TREM2 is exclusively expressed on myeloid lineage cells including dendritic cells, tissue macrophages, osteoclasts, and microglia [11,12]. Many potential ligands for TREM2 have been proposed, which are characterized based on the type of anionic and/or lipidic species, such as bacterial components, mammalian cellular membrane components and lipoproteins [15]. TREM2 interacts with the adaptor protein DNAX-activating protein 12 (DAP12)/TYRO protein kinase binding protein (TYROBP) via its transmembrane domain.…”

“…Additionally, the function of sTREM2 has not been elucidated, although elevated sTREM2 levels in CSF have been suggested to reflect microglial activation in response to neuronal degeneration [27][28][29][30][31]. In this respect, recent studies uncovered sTREM2 as not just an inactive end-product but also a signaling molecule [15] that promotes macrophage survival by preventing apoptosis [32] and activates microglia to ultimately trigger inflammatory responses and prolong survival [33]. These findings hint at the pathological implications of sTREM2 in chronic inflammation, and further elucidation of the pathophysiological roles of CSF and blood sTREM2 will provide significant novel clues on the regulation of central and systemic inflammation by targeting sTREM2 and/or sTREM2-related processes such as proteolytic production.…”