Abstract
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.