Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • Allergy (Apr 2019)
    • Biology of familial cancer predisposition syndromes (Feb 2019)
    • Mitochondrial dysfunction in disease (Aug 2018)
    • Lipid mediators of disease (Jul 2018)
    • Cellular senescence in human disease (Apr 2018)
    • View all review series...
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Scientific Show Stoppers
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication

TREM2 keeps myelinated axons under wraps

The polyanion-binding cell surface receptor TREM2 is expressed on myeloid cell populations, including microglia of the CNS. Individuals with inactivating mutations in TREM2 or TYROBP, which encodes the TREM2 adapter DAP12, develop Nasu-Hakola disease, a rare, lethal dementia that manifests in early adulthood and is characterized by demyelinating lesions. The link between loss of TREM2 function and dysfunctional myelination is not clear. Pietro Poliani, Yaming Wang, and colleagues at the University of Brescia School of Medicine used murine models to investigate a possible role for microglial TREM2 in myelin repair following injury. An age-dependent expansion of microglia was absent in the brains of mice lacking TREM2, and the microglia that were present were notably smaller and dystrophic. In a chronic toxin model of demyelination, loss of TREM2 severely impaired remyelination and removal of myelin debris during prolonged toxin exposure. Further, Trem2 deletion altered demyelination- and recovery-associated transcriptional responses, including a dysregulation of genes involved in phagocytosis, lipid transport, and inflammation. Evaluation of potential TREM2 ligands in GFP reporter cells revealed that various myelin-associated lipids activate TREM2 signaling. Together, the results of this study demonstrate that TREM2 is required for age-dependent microglia expansion and mediates remyelination following injury. The accompanying image shows representative microglia (stained with anti-Iba-1, brown) in two-year-old WT (left) and Trem2 knockout (right) mice. Note the dysmorphic appearance of microglia in the TREM2-deficient animals.

Published April 20, 2015, by Daniel Albaugh

Scientific Show StopperNeuroscience

Related articles

TREM2 sustains microglial expansion during aging and response to demyelination
Pietro Luigi Poliani, … , Susan Gilfillan, Marco Colonna
Pietro Luigi Poliani, … , Susan Gilfillan, Marco Colonna
Published May 1, 2015; First published April 20, 2015
Citation Information: J Clin Invest. 2015;125(5):2161-2170. https://doi.org/10.1172/JCI77983.
View: Text | PDF
Categories: Research Article Neuroscience

TREM2 sustains microglial expansion during aging and response to demyelination

  • Text
  • PDF
Abstract

Microglia contribute to development, homeostasis, and immunity of the CNS. Like other tissue-resident macrophage populations, microglia express the surface receptor triggering receptor expressed on myeloid cells 2 (TREM2), which binds polyanions, such as dextran sulphate and bacterial LPS, and activates downstream signaling cascades through the adapter DAP12. Individuals homozygous for inactivating mutations in TREM2 exhibit demyelination of subcortical white matter and a lethal early onset dementia known as Nasu-Hakola disease. How TREM2 deficiency mediates demyelination and disease is unknown. Here, we addressed the basis for this genetic association using Trem2–/– mice. In WT mice, microglia expanded in the corpus callosum with age, whereas aged Trem2–/– mice had fewer microglia with an abnormal morphology. In the cuprizone model of oligodendrocyte degeneration and demyelination, Trem2–/– microglia failed to amplify transcripts indicative of activation, phagocytosis, and lipid catabolism in response to myelin damage. As a result, Trem2–/– mice exhibited impaired myelin debris clearance, axonal dystrophy, oligodendrocyte reduction, and persistent demyelination after prolonged cuprizone treatment. Moreover, myelin-associated lipids robustly triggered TREM2 signaling in vitro, suggesting that TREM2 may directly sense lipid components exposed during myelin damage. We conclude that TREM2 is required for promoting microglial expansion during aging and microglial response to insults of the white matter.

Authors

Pietro Luigi Poliani, Yaming Wang, Elena Fontana, Michelle L. Robinette, Yoshinori Yamanishi, Susan Gilfillan, Marco Colonna

×
Advertisement
Follow JCI:
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts