Triggering receptor expressed on myeloid cells 2

Overview

Triggering receptor expressed on myeloid cells 2 (TREM2) is a myeloid-cell surface receptor encoded by the TREM2 gene. It is expressed prominently in cells of the innate immune system, including microglia and macrophage populations, where it participates in sensing tissue damage, regulating inflammatory responses, and supporting cell survival and differentiation. In biomedical research, TREM2 is widely studied as a disease-associated immune regulator rather than as a classical enzyme or structural protein target.

TREM2 has attracted substantial attention in neurodegeneration, especially Alzheimer’s disease, where genetic variants are associated with increased risk and altered microglial function. It is also increasingly implicated in metabolic and fibrotic disease states, including Metabolic dysfunction associated steatohepatitis and liver fibrosis, where TREM2-expressing macrophage subsets appear to contribute to disease-associated immune remodeling. Because of these roles, TREM2 is being explored both as a mechanistic biomarker and as a therapeutic target.

Focus of Latest Publications

Recent publications have examined TREM2 in several disease contexts, with a strong focus on macrophage biology, neurodegeneration, and target modulation.

In Metabolic dysfunction associated steatohepatitis (MASH), one study reported that Fe2+ deficiency blunts Trem2 expression, while restoring iron homeostasis increases emKC Trem2 abundance in the liver. This links TREM2 to iron-dependent macrophage function and suggests that labile iron starvation in embryonic Kupffer cells aggravates MASH through mitochondrial failure and macrophage dysfunction. In this context, TREM2 appears to be part of the macrophage response program that is disrupted by iron deficiency.

In liver fibrosis, another study focused on TREM2-expressing scar-associated macrophages (SAMs) and described them as integral to the pathogenesis of hepatic fibrosis. The work specifically highlighted H4K12 lactylation as a driver of TREM2high macrophage differentiation, indicating that epigenetic regulation can promote the emergence of this macrophage state during fibrotic remodeling. This places TREM2 at the center of a disease-associated macrophage differentiation pathway.

In Alzheimer’s disease, a mechanistic study examined the effects of the R47H and R62H TREM2 variants and emphasized that TREM2 plays multiple functional roles in microglia, with variants associated with increased AD risk. This aligns with the broader literature linking TREM2 to microglial responses to Beta amyloid and to disease-associated microglial states in human and experimental brain tissue, including Alzheimer's disease.

TREM2 was also the focus of a fragment-based drug discovery effort that identified a new small-molecule scaffold capable of modulating TREM2 signaling. The study described TREM2 as a relevant target in neurodegenerative diseases and cancer immunotherapy, indicating interest in pharmacologically tuning its signaling rather than simply inhibiting or activating it outright.

A separate review on gene editing and stem cell therapy for Alzheimer’s disease discussed TREM2 as one of the genetic risk factors that could be targeted using CRISPR-Cas method approaches. The review proposed that editing TREM2, alongside APOE4, may help improve the differentiation and functionality of induced pluripotent stem cells derived from AD patients, reinforcing TREM2’s importance in disease modeling and regenerative strategies.

Key Publications

Jun Labile iron starvation in embryonic Kupffer cells aggravates MASH via mitochondrial failure and macrophage dysfunction. (Cell death & disease, 2026, PMID 42310295): "Fe2+ deficiency blunts Trem2 expression, whereas restoring Fe2+ homeostasis elevates emKC Trem2 abundance in MASH liver."
Jun H4K12 lactylation drives TREM2high macrophages differentiation in liver fibrosis. (Hepatology (Baltimore, Md.), 2026, PMID 42307631): "TREM2-expressing scar-associated macrophages (SAMs) are integral to the pathogenesis of hepatic fibrosis;"
Jun Mechanisms of increased Alzheimer's disease pathology with R47H and R62H TREM2 variants. (Acta neuropathologica, 2026, PMID 42298074): "TREM2 plays multiple functional roles in microglia and variants are associated with increased risks of Alzheimer's disease (AD)."
Jun High-throughput fragment screening identifies a new small molecule scaffold that modulates TREM2 Signaling. (Bioorganic & medicinal chemistry, 2026, PMID 41793968): "...successfully identified new scaffolds that bind to triggering receptor expressed on myeloid cells 2 (TREM2), a relevant target in neurodegenerative diseases and cancer immunotherapy."
Apr Investigating the Potential of Gene Editing Technologies in Enhancing Stem Cell Therapy for Alzheimer's Disease. (Current aging science, 2026, PMID 41926312): "This review explores the potential of gene editing to target genetic risk factors associated with AD, such as APOE4 (Apolipoprotein E) and TREM2 (Triggering Receptor Expressed on Myeloid Cells 2), and to improve the differentiation and functionality of induced pluripotent stem cells (iPSCs) derived from AD patients."