TREM2 in CNS homeostasis and neurodegenerative disease

Abstract

Myeloid-lineage cells accomplish a myriad of homeostatic tasks including the recognition of pathogens, regulation of the inflammatory milieu, and mediation of tissue repair and regeneration. The innate immune receptor and its adaptor protein—triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12)—possess the ability to modulate critical cellular functions via crosstalk with diverse signaling pathways. As such, mutations in TREM2 and DAP12 have been found to be associated with a range of disease phenotypes. In particular, mutations in TREM2 increase the risk for Alzheimer's disease and other neurodegenerative disorders. The leading hypothesis is that microglia, the resident immune cells of the central nervous system, are the major myeloid cells affected by dysregulated TREM2-DAP12 function. Here, we review how impaired signaling by the TREM2-DAP12 pathway leads to altered immune responses in phagocytosis, cytokine production, and microglial proliferation and survival, thus contributing to disease pathogenesis.

Fig. 1

The TREM2-DAP12 axis modulates homeostatic functions via crosstalk with diverse signaling pathways. In the CNS, TREM2-DAP12 is preferentially expressed within microglia [32, 33]. Although signaling events need to be sequentially validated in microglia that endogenously express TREM2-DAP12, genetic depletion experiments in vitro support a multi-faceted role for TREM2-DAP12 in CNS homeostasis; TREM2-DAP12 suppresses inflammatory cytokine production following PRR-mediated recognition of PAMPs/DAMPs. LPS stimulation induces DAP12-dependent phosphorylation of Dok3 which is then recruited to the plasma membrane. There, pDok3 binds Grb2 and Sos1, thus preventing the activation of RAS and ERK, as well as the subsequent production of pro-inflammatory cytokines [68]. Similar to full-length TREM2, expression of only the TREM2-CTF leads to DAP12-dependent anti-inflammatory effects [67]. TREM2-DAP12 facilitates phagocytosis of PAMPs/DAMPs and promotes cellular debris clearance following injury or insult. Src kinase phosphorylation of the tyrosine residues of the DAP12 ITAM domain creates a docking site for Syk and downstream activation of the guanine nucleotide exchange factors Vav2/3 [74, 75] which are capable of activating Rac1/Cdc42-dependent phagocytosis and regulation of the actin cytoskeleton [60]. TREM2-DAP12 signaling synergizes with that of CSF-1R to induce a transcriptional profile reflective of enhanced myeloid cell proliferation and reduced cell death. CSF-1 via CSF-1R induces phosphorylation of DAP12 by Src kinases associated with tyrosine residue 559 of the CSF-1R, followed by DAP12-dependent phosphorylation of Syk and subsequent Pyk2-dependent activation of β-catenin-regulated pro-survival pathways [80, 81]