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Abstract
Microglia are activated after neuronal injury and in neurodegenerative diseases, and trigger neuroinflammation in the central nervous system (CNS). Microglia-derived neuroinflammation has both beneficial and detrimental effects on neurons. Because the timing and magnitude of microglial activation is thought to be a critical determinant of neuronal fate, understanding the molecular mechanisms underlying microglial activation is required to enable establishment of microglia-targeted therapies for neural diseases. Plasma membrane receptors play primary roles as activators of microglia and in this review, we focus on a receptor complex involving triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12), both of which are causative genes for Nasu-Hakola disease, a dementia with bone cysts. Recent transcriptome approaches demonstrated TREM2/DAP12 signaling as the principal regulator that transforms microglia from a homeostatic to a neural disease-associated state. Furthermore, animal model studies revealed critical roles for TREM2/DAP12 in the regulation of microglial activity, including survival, phagocytosis, and cytokine production, not only in Alzheimer's disease but also in other neural diseases, such as Parkinson's disease, demyelinating disease, ischemia, and peripheral nerve injury. Intriguingly, while TREM2/DAP12-mediated microglial activation is detrimental for some diseases, including peripheral nerve injury, it is beneficial for other diseases. As the role of activated microglia differs among disease models, TREM2/DAP12 signaling may result in different outcomes in different diseases. In this review we discuss recent perspectives on the role of TREM2/DAP12 in microglia and their contribution to neural diseases.
Highlights
Microglia are macrophage-like myeloid cells in the central nervous system (CNS)
A triggering receptor expressed on myeloid cells 2 (TREM2)/DNAX-activating protein of 12 kDa (DAP12)-mediated signal promotes proliferation, phagocytosis, and migration of microglia by induction and maintenance of microglial activation. It remains unclear whether TREM2 is a pro- or anti-inflammatory molecule
Initial studies of microglial TREM2 found that it promoted phagocytosis of apoptotic neurons and suppressed expression of pro-inflammatory molecules such as tumor necrosis factor (TNF)-α (Takahashi et al, 2005, 2007)
Summary
Microglia are macrophage-like myeloid cells in the central nervous system (CNS). Besides macrophage-related immunological functions, microglia play CNS-specific roles, such as maintenance of brain homeostasis and modulation of neural circuits (Wake et al, 2009; Paolicelli et al, 2011; Parkhurst et al, 2013; Ueno et al, 2013). The Trem2 knockout (KO) mouse demonstrated that Trem2 deficiency results in reduced microglial numbers and decreased expression of pro-inflammatory cytokines, the attenuated inflammation did not affect neuronal fate in the MPTP model (Belloli et al, 2017). Other studies transplanted TREM2-overexpressing bone marrow-derived myeloid cells (in which phagocytic activity was enhanced and pro-inflammatory gene expression was downregulated upon TREM2 stimulation) intravenously into mice with EAE (Takahashi et al, 2005, 2007).
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