TREM2 modulates neuroinflammation with elevated IRAK3 expression and plays a neuroprotective role after experimental SAH in rats

TREM2 activation alleviates neural damage via Akt/CREB/BDNF signalling after traumatic brain injury in mice

“…In ischaemic stroke, it peaks at 3–7 d [ 49 , 50 ]. In subarachnoid haemorrhage, it peaks at 48 h [ 29 ]. In our study, the expression of endogenous TREM2 peaked at 3 d after CCI in mice.…”

“…The neuroprotective effects of COG1410 after ICH were mediated by the PI3K/Akt signalling pathway [ 27 ]. In addition, TREM2 also showed an antineuroinflammatory effect in experimental ischaemic stroke and subarachnoid haemorrhage [ 28 , 29 ]. However, whether TREM2 also has neuroprotective effects after TBI has not yet been elucidated.…”

The role of triggering receptor expressed on myeloid cells-1 (TREM-1) in central nervous system diseases

“…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/βcatenin [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] region of the DAP12 junction protein. Upon binding to DAP12, tyrosine phosphorylation in ITAM mediated by Src-family kinases recruits the zeta-associated protein of 70 kDa (ZAP70) and spleen tyrosine kinase (SYK) [18], which initiates a cascade of downstream signaling reactions, including the phosphoinositide phospholipase C-gamma (PLCγ), phosphoinositide 3-kinase (PI3K), Janus kinase (JAK), and mitogen-activated protein kinase (MAPK) pathways.…”

“…TREM-1 can enhance the toll-like receptor (TLR)-4-induced inflammatory response, and TLR4 can also increase TREM-1 expression, which may be dependent on the MEK/ERK and NF-κB pathways [ 28 , 94 ]. Activation of TREM-2 can inhibit the TLR pathway via interleukin-1 receptor activated kinase 3 (IRAK3), and the activated TLR4 pathway can also inhibit TREM-2 expression at the transcriptional level and interfere with TREM-2 by cleaving it into the soluble type [ 12 , 13 ].…”

“…(still unclear) [ 6 , 7 ] HMGB1, HSP70, CD177, actin, PGLYRP1, eCIRP(see “ligands” section) Cellular debris, lipids, Aβ, nucleic acids, ApoE, LDL [ 5 , 7 – 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 – 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 ] …”