TREM family

TREM1 is known to be involved in autoimmune diseases and sepsis, whereas TREM2 receptors play a role in neurological diseases and cancer.

TREM1 amplifies the inflammatory response by acting in synergy with Toll-like receptors, which makes it a key player in diseases characterized by excessive inflammation. It is also upregulated in several autoimmune and chronic inflammatory diseases such as rheumatoid arthritis, IBD, and lupus where its expression correlates with disease severity. TREM1 is therefore primarily a target for therapeutic inhibition.

TREM2 is a double-edged regulator, expressed mainly by microglia and tissue macrophages, where it acts as a lipid and phagocytosis receptor while dampening inflammation. In Alzheimer’s disease, it plays a largely protective role: it supports microglial survival, migration and phagocytosis, promoting the clearance of neurotoxic proteins, which drives the development of agonists. Conversely, in oncology it is immunosuppressive. Depending on the disease, the goal is therefore either to activate or to block it.

Frequently studied targets include TREM1 (CD354), TREM2, and the TREM-like transcripts TREML1 (TLT-1), TREML2 (TLT-2) and TREML4 (TLT-4), along with the shared signalling adaptor DAP12 (TYROBP).

TREM-1 has a short cytoplasmic tail and therefore cannot efficiently signal on its own. It associates with the adaptor protein DAP12, which contains an ITAM (Immunoreceptor Tyrosine-based Activation Motif).

Upon receptor activation:

TREM-1 → DAP12 → ITAM phosphorylation → Syk activation → downstream signaling → inflammatory cytokine production

TREM receptors are mainly expressed by cells of the myeloid lineage, including:

• Monocytes
• Macrophages
• Neutrophils
• Dendritic cells
• Microglia
• Osteoclasts

TREM-1 is mainly associated with the amplification of inflammatory responses, whereas TREM-2 is strongly involved in myeloid-cell regulation, phagocytosis, metabolism, and tissue homeostasis. However, TREM-2 can have context-dependent effects on inflammation.

Identifying TREM ligands is essential for understanding how TREM receptors are activated and how they regulate cellular functions.

Potential TREM-1 ligands reported in the literature include PGLYRP1, HMGB1, HSP70, actin, and eCIRP, although the ligand biology remains an active area of research.