TREM2 Signaling Interactive Diagram

Microglia are cells arising from the myeloid lineage that have important roles in mediating the inflammatory response within the central nervous system (CNS). Among other tasks, microglia are responsible for the recognition and elimination of foreign invaders and the repair of local damage to CNS tissue resulting from injury. In addition, microglia play important roles in neural circuit modulation and in general homeostasis. In recent years, chronic neuroinflammation, or gliosis, has been at the forefront of studies in neurodegeneration and, as the predominant cellular mediator of neuroinflammation, microglia have been the main focus of such work. In particular, major research efforts have been directed toward elucidating the exact role played by microglia in the pathogenesis of Alzheimer’s disease (AD).

The function of a microglial receptor-adaptor complex, known as triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12), has been shown to be important in multiple neurodegenerative diseases, including AD and Parkinson’s disease. The interaction between TREM2 and DAP12 is likely to mediate several neuroinflammatory responses related to phagocytosis and debris clearance, modulation of proinflammatory cytokine production and release, and transcriptional changes to promote microglial proliferation and survival. Therefore, changes in TREM2/DAP12 function directly affect the timing and magnitude of microglial activation, which affects neuronal function and survival.

TREM2 is composed of three distinct domains. The first is an extracellular sensor containing an immunoglobulin domain that binds pathogen-associated molecular pattern molecules (PAMPs), damage-associated molecular pattern molecules (DAMPs), cell debris, lipids, and apolipoproteins. In addition, the TREM2 extracellular domain is responsive to accumulated Aβ in AD. Cleavage by enzymes from the ADAM family, ADAM10 and ADAM17, can release a secreted variant of the TREM2 extracellular domain (sTREM2) that may play a protective role in microglial survival and in propagating proinflammatory signals. The second TREM2 domain is its transmembrane domain, which associates with DAP12. The third TREM2 domain is its short cytoplasmic tail (TREM2 ICD), which is released via γ-secretase cleavage of TREM2. The function of the TREM2 ICD is unknown.

Extracellular ligand binding activates TREM2, which in turn activates DAP12, leading to a cascade of intracellular signaling events. Specifically, DAP12 contains an immunoreceptor tyrosine-based activation motif (ITAM) with tyrosine residues that become phosphorylated when TREM2 binds a ligand. This then recruits Syk kinase to activate downstream signaling molecules, such as several Vav guanine nucleotide exchange factors, the nonreceptor tyrosine kinase Pyk2, phosphatidylinositol 3-kinase (PI3K; recruited to membrane with help from DAP10), phospholipase Cγ (PLCγ), and the membrane-bound linker for T-cell activation 1 and 2 (LAT1/2). Depending on the context, these signaling cascades can be differentially and synergistically engaged, thereby affecting a variety of microglial functions that include receptor-mediated phagocytosis, transcriptional regulation mediated by β-catenin and mTOR complex 1, metabolic homeostasis through PIP2/3-mediated activation of AKT and mTOR complex 2, RAS/MEK/ERK activation leading to transcriptional regulation of pro-inflammatory molecules, and calcium modulation leading to actin remodeling.

Phosphorylation of DAP12 by the protein tyrosine kinase, Src, can exert further modulation of downstream signaling cascades. In particular, DAP12 activation in a Syk-independent, Src-dependent manner leads to inhibition of the RAS/MEK/ERK pathway via Src-dependent phosphorylation and recruitment of the adapter protein, Dok3, and its associated proteins, Grb2 and Sos1. This prevents activation of the RAS-ERK pathway, thereby decreasing the secretion of pro-inflammatory cytokines. This bimodal regulation of ERK signaling illustrates the importance of a highly regulated TREM2/DAP12 complex that is finely tuned to modulate appropriate pro-inflammatory responses. Lastly, Src phosphorylation of DAP12 mediates interaction with the lipid phosphatase, SHIP1. SHIP1 interacts with the adaptor protein CD2AP, which binds the RAB5-activating guanine nucleotide exchange factor, RIN3. RIN3, in turn, binds BIN1, a protein that is involved in endocytosis and receptor trafficking and a well-known risk locus for late-onset AD. In the AD disease state, the SHIP1/CD2A/RIN3/BIN1 complex may increase Aβ uptake and degradation by microglia. In addition to this function, new evidence suggests complex crosstalk between the membrane protein CD33 and TREM2, whereby CD33-bound SHIP1 can inhibit Syk activation and, thereby, PI3K activation, autophagy, and microglial metabolic homeostasis.

Genome-wide association studies in people with AD uncovered many disease risk loci within the TREM2/DAP12 signaling axis in microglia. Understanding functional changes of this complex and its downstream effectors will shed light on the role that microglia play in the pathogenesis of AD and other neurodegenerative diseases.

Selected Reviews:

• Colonna M, Wang Y. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat Rev Neurosci. 2016;17(4):201-7.
• Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer's disease. J Cell Biol. 2018;217(2):459-472.
• Painter MM, Atagi Y, Liu CC, et al. TREM2 in CNS homeostasis and neurodegenerative disease. Mol Neurodegener. 2015;10:43.
• Tang D, Kang R, Coyne CB, Zeh HJ, Lotze MT. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol Rev. 2012;249(1):158-75.
• Konishi H, Kiyama H. Microglial TREM2/DAP12 signaling: a double-edged sword in neural diseases. Front Cell Neurosci. 2018;12:206.
• Brantley-sieders DM, Zhuang G, Vaught D, et al. Host deficiency in Vav2/3 guanine nucleotide exchange factors impairs tumor growth, survival, and angiogenesis in vivo. Mol Cancer Res. 2009;7(5):615-23.
• Li C, Götz J. Pyk2 is a novel tau tyrosine kinase that is regulated by the tyrosine kinase Fyn. J Alzheimers Dis. 2018;64(1):205-221.
• Martelli MP, Lin H, Zhang W, Samelson LE, Bierer BE. Signaling via LAT (linker for T-cell activation) and Syk/ZAP70 is required for ERK activation and NFAT transcriptional activation following CD2 stimulation. Blood. 2000;96(6):2181-90.
• Peng Q, Malhotra S, Torchia JA, Kerr WG, Coggeshall KM, Humphrey MB. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Sci Signal. 2010;3(122):ra38.
• Tan MS, Yu JT, Tan L. Bridging integrator 1 (BIN1): form, function, and Alzheimer's disease. Trends Mol Med. 2013;19(10):594-603.
• Griciuc A, Patel S, Federico AN, et al. TREM2 acts downstream of CD33 in modulating microglial pathology in Alzheimer's disease. Neuron. 2019;103(5):820-835.e7.

We would like to thank Yuka A. Martens, Mayo Clinic, Jacksonville, FL for reviewing this pathway.

Created October 2019.