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 gamma-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 degrees 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.

Triggering receptor expressed on myeloid cells: role in the diagnosis of lung infections.

The triggering receptor expressed on myeloid cells (TREM)-1 is a recently described molecule, which plays an important role in myeloid cell-activated inflammatory responses. TREM-1 is expressed on blood neutrophils and monocytes, and also on alveolar macrophages, thus suggesting a potential role in lung inflammatory responses against infections. To investigate the differential expression of TREM-1 in lung infections, its levels were assessed in bronchoalveolar lavage specimens from patients with community-acquired pneumonia or tuberculosis. TREM-1 was also investigated in patients with interstitial lung diseases, as a model of noninfectious inflammatory disease of the lung. TREM-1 expression was significantly increased in lung neutrophils and in lung macrophages of patients with pneumonia (n=7; 387.9+/-61.4 and 660.5+/-18.3, respectively) compared with patients with pulmonary tuberculosis (n=7; 59.2+/-13.1 and 80.6+/-291.2) and patients with interstitial lung diseases (n=10; 91.8+/-23.3 and 123.9+/-22.8). In contrast, TREM-1 expression on peripheral blood neutrophils was no different among the three groups. In conclusion, these data suggest that triggering receptor expressed on myeloid cells-1 is selectively expressed in the lungs of patients with pneumonia caused by extracellular bacteria and not in patients with tuberculosis, providing a potential marker for differential diagnosis.

The C-C chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics.

In vitro polarized human Th2 cells preferentially express the chemokine receptors CCR3, CCR4, and CCR8 and migrate to their ligands: eotaxin, monocyte-derived chemokine (MDC), thymus- and activation-regulated chemokine (TARC), and I-309. We have studied the expression of chemokines and chemokine receptors in the airway mucosa of atopic asthmatics. Immunofluorescent analysis of endobronchial biopsies from six asthmatics, taken 24 hours after allergen challenge, demonstrates that virtually all T cells express IL-4 and CCR4. CCR8 is coexpressed with CCR4 on 28% of the T cells, while CCR3 is expressed on eosinophils but not on T cells. Expression of the CCR4-specific ligands MDC and TARC is strongly upregulated on airway epithelial cells upon allergen challenge, suggesting an involvement of this receptor/ligand axis in the regulation of lymphocyte recruitment into the asthmatic bronchi. In contrast to asthma, T cells infiltrating the airways of patients with chronic obstructive pulmonary disease and pulmonary sarcoidosis produce IFN-gamma and express high levels of CXCR3, while lacking CCR4 and CCR8 expression. These data support the role of CCR4, of its ligands MDC and TARC, and of CCR8 in the pathogenesis of allergen-induced late asthmatic responses and suggest that these molecules could be considered as targets for therapeutic intervention.