TREM2 regulates microglial cell activation in response to demyelination in vivo

Claudia Cantoni, Bryan Bollman, Danilo Licastro, Mingqiang Xie, Robert Mikesell, Robert Schmidt, Carla M. Yuede, Daniela Galimberti, Gunilla Olivecrona, Robyn S. Klein, Anne H. Cross, Karel Otero, Laura Piccio

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)429-447
Number of pages19
JournalActa Neuropathologica
Volume129
Issue number3
DOIs
Publication statusPublished - 2015

Keywords

  • Cuprizone-induced demyelination
  • Microglia
  • Phagocytosis
  • TREM2

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'TREM2 regulates microglial cell activation in response to demyelination in vivo'. Together they form a unique fingerprint.

Cite this