Physiology, pathology and therapeutic potential of microglial triggering receptor expressed on myeloid cells 2 signalling: A narrative update

Abstract Background Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia‐enriched surface receptor that plays a central role in sensing lipid ligands and damage‐associated molecular patterns within the central nervous system. Growing evidence has expanded our understanding of TREM2 in both physiological homeostasis and a broad range of neurological disorders, and has further identified TREM2 as a promising therapeutic target. Objective This review aims to provide an updated overview of TREM2 signaling in microglial physiology and pathology, and to summarize the therapeutic potential of TREM2‐targeted interventions across neurological diseases. Methods A narrative synthesis of recent literature was performed to examine TREM2 signaling, its context‐dependent functions in both physiological and pathological states, and emerging advances in TREM2‐targeted therapeutic strategies for neurological disorders. Key Findings Under physiological conditions, TREM2 maintains microglial survival, homeostatic surveillance, and synaptic pruning. In pathological contexts, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, and glioblastoma, TREM2 signaling regulates microglial activation, promotes the clearance of pathological substrates, and shapes neuroinflammatory responses. Conclusions TREM2‐mediated microglial responses are highly context dependent and may exert distinct or even opposing functions across different disease types. A major challenge for future research is to tailor TREM2‐based interventions to the specific disease context, timing, and microenvironment in order to maximize their neuroprotective and immunomodulatory effects.