Fig. 1

TREM-1 signaling pathway. Two isoforms of TREM-1 exist: the membrane-bound type (mTREM-1) and the soluble type (sTREM-1). mTREM-1 is located on the plasma membrane, and its extracellular immunoglobulin(Ig)-like domain is responsible for recognizing ligands such as pathogen-associated molecular patterns and danger-associated molecular patterns. After activation, the transmembrane (TM) domain transmits signals intracellularly by binding to the adapter molecule DAP12. Upon binding, tyrosine phosphorylation in immunoreceptor tyrosine-based activation motif (ITAM) that is mediated by Src-family kinases recruits the zeta-associated protein of 70 kDa (ZAP70) and spleen tyrosine kinase (SYK), thereby initiating a cascade of downstream signalization, including the activation of the phosphoinositide phospholipase C-gamma (PLCγ), phosphoinositide 3-kinases (PI3K), Janus kinase (JAK), and mitogen-activated protein kinases (MAPK) pathways. These pathways induce Ca²⁺ mobilization, actin cytoskeleton rearrangement, and activation of transcription factors, which are responsible for encoding the expression of inflammatory mediators. Metalloproteinases (MMPs) can cleave mTREM-1 into the soluble form, which competes with mTREM-1 for the same ligands and blocks mTREM-1 signaling. Decoy peptides that have been developed for the TREM-1 ligand-binding domain include LP17, LR12, and M3, while GF9 is an inhibitor that targets the transmembrane structural domains of TREM-1. All of these can block mTREM-1 and inhibit the activity of the inflammatory pathway. In addition to the inflammatory pathway, TREM-1 induces pyroptosis through the NLRP3/Caspase-1 signaling pathway and participates in oxidative stress through ROS release. The above pathways together contribute to neuronal damage