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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
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Microglia regulate cortical remyelination via TNFR1-dependent phenotypic polarization

Athena Boutou1, Ilias Roufagalas1, Katerina Politopoulou1

  • 1Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 11521 Athens, Greece.

Cell Reports
|October 24, 2024
PubMed

Insights

Targeting tumor necrosis factor receptor 1 (TNFR1) and related inflammatory pathways in microglia promotes central nervous system (CNS) remyelination and motor recovery in neurodegenerative diseases.

Area of Science:

  • Neuroimmunology
  • Neurobiology
  • Cellular Biology

Background:

  • Microglia are key immune cells in the central nervous system (CNS) implicated in demyelinating diseases.
  • Understanding the mechanisms controlling CNS remyelination is crucial for treating neurodegenerative disorders.
  • The precise roles of microglia in promoting or hindering CNS repair remain incompletely understood.

Purpose of the Study:

  • To investigate the role of tumor necrosis factor receptor 1 (TNFR1) and associated inflammatory pathways in microglia-mediated CNS repair.
  • To determine if modulating microglial inflammatory responses can enhance remyelination and motor function recovery.

Main Methods:

  • Microglia-specific deletion of TNFR1 in a disease model.
  • Pharmacological inhibition of soluble TNF (solTNF) and IL-1R.
  • Single-cell transcriptomic analysis of the cortex.
  • Longitudinal brain transcriptome analysis.
  • In vivo validation of microglial inflammatory polarization pathways.

Main Results:

  • Microglia-specific deletion of TNFR1 and inhibition of solTNF or IL-1R promoted maturation of disease-associated microglia with enhanced myelin phagocytosis.
  • These interventions accelerated cortical remyelination and improved motor recovery.
  • SolTNF inhibition shifted microglia towards reparative IL-10-responsive signatures while reducing damaging IL-1-related pathways.
  • Earlier recovery was observed with therapeutic loss of microglia TNFR1.
  • Disease-state microglia targeting IL-1/IL-18/caspase-11 were identified in human demyelinating lesions.

Conclusions:

  • Modulating microglial inflammatory polarization by targeting cytokines like TNF and IL-1 is a promising therapeutic strategy.
  • This approach can enhance CNS repair and functional recovery in demyelinating disorders.
  • Targeting microglial TNFR1 and downstream inflammatory pathways offers a potential avenue for improving remyelination.
Keywords:
CP: ImmunologyCP: NeuroscienceDAMIL-1TNFdemyelinationmicrogliamultiple sclerosisneuroinflammationneuromyelitis opticaoligodendrocyte differentiationremyelination

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