Abstract
DNAX-activating protein of 12 kDa (DAP12) is a signaling adapter protein expressed in cells that participate in innate immune responses. By pairing with different triggering receptors expressed on myeloid cell (TREM) proteins, DAP12 can mediate both positive and negative cellular responses. In particular, TREM1 acts as an amplifier of the immune response, while TREM2 functions as a negative regulator. TREM2 has also been shown to stimulate the phagocytosis of apoptotic neurons and define the barrier function in microglia. Notably, loss-of-function mutations of either DAP12 or TREM2 result in a disorder known as Nasu-Hakola disease (NHD); and mutations of these genes have been associated with the risk for Alzheimer’s disease (AD), suggesting that TREM2 and DAP12 may regulate common signaling pathways in the disease pathogenesis. In this study, we demonstrated an anti-inflammatory role of DAP12 in murine microglia that depends on the presence of TREM2. We also uncovered the JNK signaling pathway as the underlying molecular mechanism by which the TREM2/DAP12 complex suppresses the hyperactivation of microglia upon LPS stimulation. Interestingly, LPS down-regulates the expression of Trem2 via the activation of JNK and NF-κB signaling pathways, resulting in a vicious cycle that synergistically promotes the inflammatory responses. Our study provides insights into mechanism-based therapy for neuroinflammatory disorders.
Highlights
DNAX-activating protein of 12 kDa (DAP12; known as TYROBP and KARAP) is a signaling adapter protein expressed by a variety of innate immune cells including macrophages, microglia, monocytes, dendritic cells and natural killer (NK) cells (Lanier, 2009)
Since we observed an anti-inflammation function of DAP12 in microglia, we further investigated whether DAP12 suppresses the production of inflammatory cytokines in a manner that depends on TREM2
Primary microglia were isolated from both WT and Trem2-knockout (KO) mice and further subjected to siRNA treatment that knock down the expression of Dap12 (Figure 2A)
Summary
DNAX-activating protein of 12 kDa (DAP12; known as TYROBP and KARAP) is a signaling adapter protein expressed by a variety of innate immune cells including macrophages, microglia, monocytes, dendritic cells and natural killer (NK) cells (Lanier, 2009). DAP12 consists of a minimal extracellular domain, a transmembrane segment and a cytoplasmic region containing a single immunoreceptor tyrosine-based activation motif (ITAM). An aspartic acid in the transmembrane domain of DAP12 allows its association with cell surface receptors via an electrostatic interaction. The receptors usually have an oppositely charged amino acid (arginine or lysine) embedded within their transmembrane region that allows the formation of non-covalent complexes with DAP12 (Lanier and Bakker, 2000; Humphrey et al, 2005). Triggering receptors expressed on myeloid cells (TREMs) are a family of cell surface receptors expressed broadly on myeloid cells that have been identified to associate with DAP12 (Bouchon et al, 2000; Daws et al, 2001; Chung et al, 2002). TREM1 is a potent amplifier of the inflammatory responses; while TREM2 has an anti-inflammatory function (Bouchon et al, 2000; Gibot et al, 2004; Takahashi et al, 2005; Turnbull et al, 2006)
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