TREM2-mediated regulation of microglial activity: a promising target for the treatment of ischemic stroke

Abstract

Ischemic stroke, the most prevalent type of stroke globally, poses significant challenges due to its high incidence, morbidity, and long-term disability. Microglia, the resident immune cells of the central nervous system (CNS), play a dual role in the context of ischemic stroke. While they contribute to neuroinflammation by releasing pro-inflammatory cytokines and exacerbating neuronal injury, they also facilitate tissue repair, angiogenesis, and restoration of the blood-brain barrier (BBB) integrity through the secretion of anti-inflammatory and neurotrophic factors. Triggering receptor expressed on myeloid cells 2 (TREM2), predominantly expressed on microglia, is a critical regulator of microglial proliferation, survival, phagocytosis, polarization, inflammation, and metabolism. TREM2 has emerged as a key modulator of immune responses in ischemic stroke. This review provides a comprehensive examination of the multifaceted roles of TREM2 in microglial biology during ischemic stroke, integrating current insights into its molecular mechanisms. Furthermore, it highlights TREM2's potential as a transformative therapeutic target, advancing our understanding of neuroimmune regulation and promoting recovery after stroke.

Keywords: Ischemic stroke; Microglia; Neuroinflammation; Therapeutic target; Triggering receptor expressed on myeloid cells 2 (TREM2).

Fig. 1

The role of microglia in ischemic stroke. After the onset of ischemic stroke, homeostatic microglia become activated. Depending on the surrounding environment and stimulating factors, microglia can differentiate into pro-inflammatory type or anti-inflammatory type. Activated pro-inflammatory microglia produce pro-inflammatory mediators such as TNF-α, IL-1β, IL-6, ROS, and iNOS, which exacerbate neuroinflammation, disrupt the blood-brain barrier, induce oxidative stress, and lead to neuronal death. In contrast, activated anti-inflammatory microglia secrete anti-inflammatory cytokines, including TGF-β, IL-4, IL-10, IL-13, and BDNF, which help alleviate inflammation, support neuronal survival, and maintain brain tissue homeostasis

Fig. 2

Molecular structure and partial signaling pathways of TREM2. TREM2 comprises three distinct domains: an extracellular V-type immunoglobulin domain, a transmembrane domain, and a cytoplasmic tail. sTREM2 is released by cleaving the N-terminal extracellular structure of full-length TREM2 through ADAM10/ADAM17. The remaining C-terminus can be further cleaved by γ-secretase to produce a short intracellular peptide. TREM2 can bind to various ligands, including Aβ, APOE, phospholipids, cell debris, nucleic acids/nucleic acid fragments, and others. This binding subsequently activates downstream adapter proteins DAP12 or DAP10 for signal transduction. The ITAM motif of DAP12 can be phosphorylated by SRC family kinases, which then recruit SYK. Phosphorylation of LAT1 by SYK leads to the recruitment of various signaling mediators and adaptors, activating downstream signaling pathways. The YINM motif of DAP12 binds to PI3K, promoting its activation and facilitating the conversion of PIP2 to PIP3. The activated PLCγ further catalyzes the conversion of PIP2 into IP3 and DAG, while PI3K also activates AKT. Activation of these signaling pathways can produce broad biological effects, influencing the functions of microglial cells

Fig. 3

The role of TREM2 in ischemic stroke and therapeutic strategies. TREM2 can be activated through various approaches, including TREM2 agonists and activators, traditional Chinese medicine interventions, gene therapy, and other therapeutic strategies, which induce microglial cell proliferation, enhance their phagocytic function, suppress inflammation, and promote oxidative phosphorylation and lipid metabolism in microglia. These effects contribute to improved outcomes in ischemic stroke