page 647, Takahashi et al. connect this disease to defects in phagocytic cells that are required for removal of apoptotic cells and suppression of inflammation in the brain.
The link to disease involves the TREM2 (triggering receptor expressed on myeloid cells-2) receptor and its associated adaptor protein DAP12, both known to be mutated in patients with Nasu-Hakola disease. TREMs are orphan receptors that associate with DAP12 to transmit signals in a variety of myeloid cells. The signals are primarily stimulatory: TREM1 signaling activates macrophages and neutrophils and can amplify Toll-like receptor signals, and TREM2 activates immature dendritic cells. TREM2 is also expressed on microglial cells (phagocytic cells in the brain that remove apoptotic cells and debris from the brain), but its function on these cells had not been examined until now.
Intrigued by the connection between TREM2 and Nasu-Hakola disease, Takahashi and colleagues examined the function of this molecule on primary murine microglial cells. They found that TREM2 ligation triggered phagocytosis of beads and apoptotic neurons in a process that required actin reorganization and the activation of the signaling molecule Erk. TREM2-stimulated phagocytosis did not coincide with activation of the cell or secretion of proinflammatory cytokines.
Impaired phagocytosis in the absence of TREM2 or functional DAP12 confirmed their role in phagocytosis. This experiment, however, also revealed a more striking finding. The loss of TREM2 provoked the microglial cells into producing inflammatory cytokines such as TNF and IL-1β, suggesting that TREM2 signals actively interfere with these pathways under normal circumstances. When TREM2 is missing, the lack of interference may explain the defective phagocytosis and aberrant activation of microglial cells that accompanies the buildup of cellular debris in the brain.