TY - JOUR
T1 - Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia
AU - Sessa, Giuseppina
AU - Podini, Paola
AU - Mariani, Margherita
AU - Meroni, Alessandra
AU - Spreafico, Roberto
AU - Sinigaglia, Francesco
AU - Colonna, Marco
AU - Panina, Paola
AU - Meldolesi, Jacopo
PY - 2004/11
Y1 - 2004/11
N2 - Together with its adaptor protein, the adaptor protein of 12 kDa also known as KARAP and TYROBP (DAP12), triggering receptor expressed in myeloid cells 2 (TREM2) is a stimulatory membrane receptor of the immunoglobulin/lectin-like superfamily, well known in myeloid cells. In humans, however, loss-of-function mutations of TREM2/DAP12 leave myeloid cells unaffected but induce an autosomal recessive disease characterized, together with bone cysts, by a spectrum of pathological lesions in the cortex, thalamus and basal ganglia with clinical symptoms of progressive dementia (polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy). Nothing was known about the role of TREM2/DAP12 in brain cell biology and physiology. By confocal immunocytochemistry we demonstrate that, in both human and mouse cerebral cortex, TREM2/DAP12, strongly expressed by microglia, is also present in a fraction of neurons but not in astrocytes and oligodendrocytes. In contrast, in the hippocampal cortex TREM2-expressing neurons are rare. Both in neurons and microglia the receptor appears to be located mostly intracellularly in a discrete compartment(s) partially coinciding with (or adjacent to) the Golgi complex/trans-Golgi network. Four nerve cell lines were identified as expressing the intracellular receptor system. In living human microglia CHME-5 and glioblastoma T98G cells, activation of TREM2 by its specific antibody induced [Ca2+]i responses, documenting its surface expression and functioning. Surface expression of TREM2, low in resting CHME-5 and T98G cells, increases significantly and transiently (60 min) when cells are stimulated by ionomycin, as revealed by both surface biotinylation and surface immunolabeling, Our results provide the first information about the expression, distribution (mostly intracellular) and functioning of TREM2/DAP12 system in nerve cells, a necessary step in the understanding of the cellular mechanisms affected in polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy.
AB - Together with its adaptor protein, the adaptor protein of 12 kDa also known as KARAP and TYROBP (DAP12), triggering receptor expressed in myeloid cells 2 (TREM2) is a stimulatory membrane receptor of the immunoglobulin/lectin-like superfamily, well known in myeloid cells. In humans, however, loss-of-function mutations of TREM2/DAP12 leave myeloid cells unaffected but induce an autosomal recessive disease characterized, together with bone cysts, by a spectrum of pathological lesions in the cortex, thalamus and basal ganglia with clinical symptoms of progressive dementia (polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy). Nothing was known about the role of TREM2/DAP12 in brain cell biology and physiology. By confocal immunocytochemistry we demonstrate that, in both human and mouse cerebral cortex, TREM2/DAP12, strongly expressed by microglia, is also present in a fraction of neurons but not in astrocytes and oligodendrocytes. In contrast, in the hippocampal cortex TREM2-expressing neurons are rare. Both in neurons and microglia the receptor appears to be located mostly intracellularly in a discrete compartment(s) partially coinciding with (or adjacent to) the Golgi complex/trans-Golgi network. Four nerve cell lines were identified as expressing the intracellular receptor system. In living human microglia CHME-5 and glioblastoma T98G cells, activation of TREM2 by its specific antibody induced [Ca2+]i responses, documenting its surface expression and functioning. Surface expression of TREM2, low in resting CHME-5 and T98G cells, increases significantly and transiently (60 min) when cells are stimulated by ionomycin, as revealed by both surface biotinylation and surface immunolabeling, Our results provide the first information about the expression, distribution (mostly intracellular) and functioning of TREM2/DAP12 system in nerve cells, a necessary step in the understanding of the cellular mechanisms affected in polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy.
KW - Human/mouse brain
KW - Immunoglobulin lectin-like receptor superfamily
KW - Microglia
KW - Microglia/neuroblastoma cell lines
KW - Neurons
UR - http://www.scopus.com/inward/record.url?scp=9644307970&partnerID=8YFLogxK
U2 - 10.1111/j.1460-9568.2004.03729.x
DO - 10.1111/j.1460-9568.2004.03729.x
M3 - Article
C2 - 15548205
AN - SCOPUS:9644307970
SN - 0953-816X
VL - 20
SP - 2617
EP - 2628
JO - European Journal of Neuroscience
JF - European Journal of Neuroscience
IS - 10
ER -