The biology of TREM receptors

Abstract

Triggering receptors expressed on myeloid cells (TREMs) encompass a family of cell-surface receptors chiefly expressed by granulocytes, monocytes and tissue macrophages. These receptors have been implicated in inflammation, neurodegenerative diseases, bone remodelling, metabolic syndrome, atherosclerosis and cancer. Here, I review the structure, ligands, signalling modes and functions of TREMs in humans and mice and discuss the challenges that remain in understanding TREM biology.

Fig. 1. General structure of the TREM molecules.

A three-dimensional model of the structure of the triggering receptors expressed on myeloid cells (TREMs), based on the three-dimensional TREM2 structure predicted by AlphaFold. The extracellular region of the TREMs consists of an IgV fold on a long stalk. The N terminus leader sequence and the C terminus transmembrane and cytoplasmic domains are also depicted.

Fig. 2. Human and mouse TREM gene clusters.

The triggering receptor expressed on myeloid cell (TREM) gene clusters are located on human chromosome 6p21.1 and mouse chromosome 17C. Both clusters include genes encoding TREM1, TREM2, TREML1, TREML2 and TREML4. The human cluster includes NCR2, which encodes NKp44, a receptor expressed on natural killer cells and group 3 innate lymphoid cells. The mouse cluster contains additional genes encoding TREM3, TREM4, TREM5 and TREML6. Genes highlighted in green associate with DNAX-activating protein 12 kDa (DAP12), although TREM2 also associates with DAP10. TREML6 (gene indicated in red) is a bona fide inhibitory receptor with cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. TREML1 (gene highlighted in yellow) contains a cytoplasmic motif similar to an immunoreceptor tyrosine-based inhibitory motif but delivers activating signals. The signalling properties of TREML2 (gene highlighted in grey) remain unknown. Arrows indicate the orientation of the gene. For additional details, see ref. .

Fig. 3. TREM activating signals through DAP12 and DAP10.

Engagement of activating triggering receptors expressed on myeloid cells (TREMs) by specific ligands triggers phosphorylation of the immunoreceptor tyrosine-based activation motifs (ITAMs) located in the cytosolic domain of homodimeric DNAX-activating protein 12 kDa (DAP12) by an SRC kinase family member. The phosphorylated ITAMs recruit the protein tyrosine kinase SYK, which is also phosphorylated and activated by the SRC kinase. SYK activates multiple downstream targets and scaffolds, including phosphatidylinositol 3-kinase (PI3K) comprising the p110 and p85 subunits (part a), the adapter linker for activation of T cells family member 2 (LAT2) (parts b,c) and β2 integrins (part d). In part a, PI3K activates AKT, which in turn activates mechanistic target of rapamycin (mTOR) signalling. AKT also phosphorylates glycogen synthase kinase 3β (GSK3β), resulting in GSK3β inactivation, stabilization of β-catenin and cell cycling. In part b, LAT2 phosphotyrosines form docking sites for phospholipase Cγ2 (PLCγ2), which degrades phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂) into inositol 1,4,5-triphosphate (Ins(1,4,5)P₃) and diacylglycerol (DAG) to elicit Ca²⁺ mobilization and NF-κB activation, respectively. In part c, LAT2 phosphotyrosines also form docking sites for the adaptors GRB2 and SLP76. These adaptors initiate the mitogen-activated protein kinase (MAPK) pathway and recruit guanine exchange factors of the VAV family, which promote rearrangement of the actin cytoskeleton. In part d, β2 integrins require SYK signals to acquire an open and active conformation that can bind to ligands. TREM2 and perhaps other DNAX-activating protein 12 kDa (DAP12)-associated TREMs also recruit homodimeric DAP10, which contains an YXNM motif that directly recruits the p85 subunit of PI3K and the adapter GRB2, activating the pathways highlighted earlier. Of note, signalling pathways presented here are generalized and may vary depending on the TREM, the cell type in which the receptor is expressed and the physiological or pathological context. PtdIns(3,4,5)P₃, phosphatidylinositol 3,4,5-trisphosphate.

Fig. 4. TREM-modulating signals through DAP12.

DNAX-activating protein 12 kDa (DAP12) can deliver inhibitory signals that modulate Toll-like receptor (TLR) signalling. In part a, DAP12 immunoreceptor tyrosine-based activation motifs (ITAMs) bind the phosphotyrosine-binding domain of downstream of kinase 3 (DOK3), which in turn recruits the adapters GRB2 and SOS, subtracting them from TLRs and thereby interfering with the capacity of TLRs to initiate extracellular signal-regulated kinase (ERK) signalling. In part b, DAP12 and DOK3 can also recruit the inositol phosphatase SHIP1, which degrades phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P₃) to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂), regulating the recruitment and activation of intracellular signalling molecules tethered to the membrane through PtdIns(3,4,5)P₃.