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Acute microglia ablation induces neurodegeneration in the somatosensory system
Stephen J Rubino1, Lior Mayo1,2, Isabella Wimmer3
1Ann Romney Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, MA, USA.
Abstract:
Previous studies have reported that microglia depletion leads to impairment of synapse formation and these cells rapidly repopulate from CNS progenitors. However, the impact of microglia depletion and repopulation in the long-term state of the CNS environment has not been characterized. Here, we report that acute and synchronous microglia depletion and subsequent repopulation induces gray matter microgliosis, neuronal death in the somatosensory cortex and ataxia-like behavior. We find a type 1 interferon inflammatory signature in degenerating somatosensory cortex from microglia-depleted mice. Transcriptomic and mass cytometry analysis of repopulated microglia demonstrates an interferon regulatory factor 7-driven activation state. Minocycline and anti-IFNAR1 antibody treatment attenuate the CNS type 1 interferon-driven inflammation, restore microglia homeostasis and reduce ataxic behavior. Neither microglia depletion nor repopulation impact neuropathology or T-cell responses during experimental autoimmune encephalomyelitis. Together, we found that acute microglia ablation induces a type 1 interferon activation state of gray matter microglia associated with acute neurodegeneration.
Insights
Acute microglia depletion and repopulation cause gray matter inflammation and neuronal death, linked to a type 1 interferon signature. Treatments targeting this pathway show promise in restoring brain homeostasis and reducing behavioral deficits.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the resident immune cells of the central nervous system (CNS), are crucial for brain health.
- Previous research indicates microglia depletion impairs synapse formation and that these cells repopulate from CNS progenitors.
- The long-term consequences of microglia depletion and subsequent repopulation on the CNS environment remain incompletely understood.
Purpose of the Study:
- To investigate the long-term effects of acute microglia depletion and repopulation on the CNS.
- To identify the molecular mechanisms underlying neuroinflammation and neurodegeneration following microglia ablation.
- To evaluate therapeutic strategies for mitigating adverse effects of microglia repopulation.
Main Methods:
- Acute and synchronous depletion of microglia in a mouse model.
- Repopulation of microglia from CNS progenitors.
- Analysis of gray matter, neuronal survival in the somatosensory cortex, and behavioral assessments (ataxia).
- Transcriptomic and mass cytometry analysis of repopulated microglia.
- Treatment with minocycline and anti-IFNAR1 antibody.
Main Results:
- Microglia depletion and repopulation induced gray matter microgliosis, neuronal death in the somatosensory cortex, and ataxia-like behavior.
- A type 1 interferon inflammatory signature was identified in the degenerating cortex.
- Repopulated microglia exhibited an interferon regulatory factor 7 (IRF7)-driven activation state.
- Minocycline and anti-IFNAR1 antibody treatment reduced type 1 interferon-driven inflammation, restored microglia homeostasis, and ameliorated ataxic behavior.
- Microglia dynamics did not affect neuropathology or T-cell responses in experimental autoimmune encephalomyelitis (EAE).
Conclusions:
- Acute microglia ablation triggers a type 1 interferon activation state in gray matter microglia.
- This activation state is associated with acute neurodegeneration and behavioral deficits.
- Targeting type 1 interferon pathways offers a potential therapeutic approach for neuroinflammatory conditions involving microglia dysregulation.
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