title: TREM2 regulates microglial cell activation in response to demyelination in vivo.
abstract: Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage.
authors: Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St Louis, MO, 63110, USA.
authors: Claudia
authors: C
authors: Cantoni
authors: Bryan
authors: B
authors: Bollman
authors: Danilo
authors: D
authors: Licastro
authors: Mingqiang
authors: M
authors: Xie
authors: Robert
authors: R
authors: Mikesell
authors: Robert
authors: R
authors: Schmidt
authors: Carla M
authors: CM
authors: Yuede
authors: Daniela
authors: D
authors: Galimberti
authors: Gunilla
authors: G
authors: Olivecrona
authors: Robyn S
authors: RS
authors: Klein
authors: Anne H
authors: AH
authors: Cross
authors: Karel
authors: K
authors: Otero
authors: Laura
authors: L
authors: Piccio
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002614:Chelating Agents / Q000633:toxicity; D003471:Cuprizone / Q000633:toxicity; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D016253:Microscopy, Immunoelectron; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000378:metabolism*
chemical_list: D002614:Chelating Agents; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse; D003471:Cuprizone
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