Table 1 The similarities and differences between TREM-1 and TREM-2 in CNS diseases

Structure

Composed of three parts: the extracellular immunoglobulin-like domain, the transmembrane domain and the cytoplasmic domain

Two subtypes exist: the membrane-bound type and the soluble type [3,4,5]

Enzyme: MMPs

Enzyme: ADAM 10 and ADAM 17 [5]

Ligands

PAMPs? DAMPs? (still unclear) [6, 7]

HMGB1, HSP70, CD177, actin, PGLYRP1, eCIRP(see “ligands” section)

Cellular debris, lipids, Aβ, nucleic acids, ApoE, LDL [5, 7,8,9]

Signaling Pathways

The transmembrane domain undergoes signaling by binding to DAP12 containing the ITAM. ITAM is phosphorylated by Src-family kinase, and recruits Syk to trigger downstream signaling cascades, including PI3K/Akt and MEK/ERK [3,4,5]

Promote inflammation: JAK-STAT3/5, MEK/ERK, PI3K/Akt, NF-κB [6, 128];

Inhibit apoptosis: PI3K/Akt [6];

Promote pyroptosis: NLRP3/caspase-1 [84, 85, 100];

Induce oxidative stress: ROS [84, 127];

Interact with the TLR4 pathway to enhance inflammation [28, 94]

Except DAP12, TREM-2 can also bind to DAP10 [5];

Promote phagocytosis and

actin cytoskeleton rearrangement: VAV2/3-Rac1/Cdc42-Arp2/3 [7];

Promote cell growth: Pyk2/β-catenin [7];

Inhibit inflammation: Inhibit NF-κB and MEK/ERK [7, 10];

Inhibit Autophagy: PI3K/Akt-mTOR [11];

Mutual inhibition with the TLR4 pathway [12, 13]