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Microglial clock dysfunction during neuroinflammation impairs oligodendrocyte progenitor cell recruitment and
Qingqing Lu1,2, Jin Young Kim1,2
1Department of Biomedical Sciences, College of Biomedicine, City University of Hong Kong, Hong Kong, Hong Kong SAR, China.
Introduction:
Circadian clocks generate daily physiological rhythms and regulate immune functions, including cytokine production and inflammatory responses. Although time-of-day-dependent variation in microglial immune activity has been reported, how intrinsic microglial clocks respond to neuroinflammatory stimuli and influence microglial function remains unclear.
Methods:
We induced neuroinflammation via intraperitoneal injection of lipopolysaccharide (LPS) and isolated microglia from control and LPS-treated mouse brains. To examine circadian clock dynamics and downstream targets, we performed time-series gene expression analyses. To assess the functional relevance of microglial clocks, we transplanted either wild-type or Bmal1-deleted microglia, as well as control or neuroinflammatory microglia, into the corpus callosum of NG2DsRed reporter mice and evaluated oligodendrocyte progenitor cell (OPC) recruitment.
Results:
LPS-induced neuroinflammation triggered a phase shift in the core clock gene Bmal1 and disrupted the rhythmic expression of its targets, including Per1, Iba1, Itgam, and Ccl5, resulting in sustained microglial activation. Transplanted wild-type microglia effectively recruited OPCs, whereas both Bmal1-deleted and neuroinflammatory microglia failed to recruit OPCs, indicating that disrupted microglial clock function promotes persistent activation and impairs glial-glial communication.
Discussion:
These findings identify microglial circadian clocks as key regulators of homeostatic function and glial-glial communication. Preserving intrinsic clock function in microglia may represent a strategy to mitigate neuroinflammatory damage and support white matter integrity.
Insights
Neuroinflammation disrupts microglial circadian clocks, leading to sustained activation and impaired communication. Preserving microglial clock function is crucial for mitigating neuroinflammation and supporting white matter health.
Area of Science:
- Neuroscience
- Immunology
- Chronobiology
Background:
- Circadian clocks regulate daily physiological rhythms and immune functions, including microglial activity.
- The precise mechanisms by which microglial circadian clocks respond to neuroinflammation and affect microglial function are not fully understood.
Purpose of the Study:
- To investigate how neuroinflammation impacts microglial circadian clock dynamics.
- To determine the functional consequences of disrupted microglial clock function on microglial activation and glial-glial communication.
Main Methods:
- Neuroinflammation was induced in mice using lipopolysaccharide (LPS).
- Time-series gene expression analysis was performed on isolated microglia to assess circadian clock gene expression.
- Wild-type or Bmal1-deleted microglia, and control or neuroinflammatory microglia, were transplanted into reporter mice to evaluate oligodendrocyte progenitor cell (OPC) recruitment.
Main Results:
- LPS-induced neuroinflammation caused a phase shift in the core clock gene Bmal1 and disrupted the rhythmic expression of its targets, leading to sustained microglial activation.
- Transplanted wild-type microglia successfully recruited OPCs.
- Both Bmal1-deleted and neuroinflammatory microglia failed to recruit OPCs, indicating impaired glial-glial communication.
Conclusions:
- Microglial circadian clocks are critical regulators of homeostatic function and glial-glial communication.
- Disrupted microglial clock function contributes to persistent microglial activation and impaired white matter repair.
- Maintaining intrinsic microglial clock function may be a therapeutic strategy for neuroinflammatory conditions.
