Triggering receptor expressed in myeloid cells 2 (TREM2) trafficking in microglial cells: Continuous shuttling to and from the plasma membrane regulated by cell stimulation

Cell biology of triggering receptor expressed in myeloid cells 2, a receptor expressed in brain cells (microglia and possibly neurons and oligodendrocytes) which is responsible for a neurological and psychiatric genetic disease, polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy otherwise called the Nasu-Hakola disease, is still largely unknown. Using immortalized mouse N9 microglial cells we demonstrate that triggering receptor expressed in myeloid cells 2 is mostly distributed intracellularly in two pools: a deposit in the Golgi complex and a population of exocytic vesicles, distinct from endosomes and lysosomes, which is continuously translocated to, and recycled from the cell surface. Results with ionomycin and γ-interferon, showing rapid and slow increases, respectively, of triggering receptor expressed in myeloid cells 2 surface density, documented that the exocytosis of the receptor-rich vesicles is regulated. Pulse labeling in the cold of surface triggering receptor expressed in myeloid cells 2 with its antibody (or Fab fragment) followed by chase at 37 °C showed internalization, with recovery of the antibody in endosomes and lysosomes. However, part of the receptor/antibody complex, internalized for up to 30 min chase, was recycled to the cell surface within 2 min of ionomycin stimulation, together with a fraction of the total biotinylated surface protein chased in parallel. The internalized receptor appears therefore to get access to exocytic organelles distinct from lysosomes which may resemble the exocytic vesicles of resting cells. These results document that, in microglial cells, the surface density of the triggering receptor expressed in myeloid cells 2 and thus, presumably, the response to its activation, is continuously adapted and can be greatly increased, even at rapid rate, as a function of cell activation.