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Related Experiment Video

Updated: May 10, 2025

Intravital Imaging of Axonal Interactions with Microglia and Macrophages in a Mouse Dorsal Column Crush Injury
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Microglia endotoxin tolerance is retained after enforced repopulation.

Tiago Medeiros-Furquim1, Anneke Miedema1, Edwin Schilder1

  • 1Department of Biomedical Sciences, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Brain, Behavior, and Immunity
|April 24, 2025
PubMed
Summary

Microglia develop innate immune memory, a state called endotoxin tolerance, which persists even after depletion and repopulation. This finding impacts the clinical use of microglia-depleting strategies for brain diseases.

Keywords:
BLZ945CSF1RCSF1R-inhibitorDepletionEndotoxin toleranceInnate immune memoryMicrogliaNeuroinflammationRepopulationSotuletinib

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Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Microglia, the brain's immune cells, are vital for central nervous system (CNS) homeostasis.
  • Systemic inflammation can influence microglia, potentially contributing to neurodegeneration.
  • Microglia, like other innate immune cells, can develop innate immune memory (IIM), altering responses to subsequent inflammatory stimuli.

Purpose of the Study:

  • To investigate if microglia depletion-repopulation can reverse lipopolysaccharide (LPS)-induced endotoxin tolerance in mice.
  • To understand the functional and molecular state of repopulated microglia.

Main Methods:

  • Utilized BLZ945, a colony-stimulating factor 1 receptor inhibitor, to deplete microglia in mice.
  • Induced endotoxin tolerance using LPS preconditioning.
  • Analyzed gene expression profiles of repopulated microglia, focusing on homeostasis, metabolism, and immune response genes.

Main Results:

  • Repopulated microglia showed altered gene expression, with reduced homeostatic and mitochondrial respiration genes but increased immune activation genes.
  • Despite repopulation, the blunted inflammatory response characteristic of LPS-induced endotoxin tolerance persisted.
  • This suggests that endotoxin tolerance in microglia is resistant to reversal by depletion-repopulation strategies.

Conclusions:

  • Microglia endotoxin tolerance demonstrates remarkable persistence following a depletion-repopulation cycle.
  • Strategies involving microglia depletion may have limited effectiveness in restoring normal microglial function in conditions involving prior inflammatory challenges.
  • Further research is needed to understand the mechanisms maintaining this persistent tolerance and its implications for neurodegenerative diseases.