Microglial Clock Dysfunction During Neuroinflammation Impairs Oligodendrocyte Progenitor Cell Recruitment and Disrupts Neuroimmune Homeostasis

Qingqing LuJin Young Kim^*

• City University of Hong Kong, Kowloon, Hong Kong, SAR China

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. Here, we show that neuroinflammation disrupts microglial circadian clocks and impairs key homeostatic functions. We induced neuroinflammation via intraperitoneal injection of lipopolysaccharide (LPS), then purified microglia from control and LPS-treated mouse brains for time-series gene expression analysis. Neuroinflammation induced a phase shift in the circadian transcription factor Bmal1 and abolished rhythmic expression of its targets, including won inhibitor Per1, microglial activation markers Iba1 and Itgam, and the cytokine Ccl5, resulting in sustained microglial activation. Transplantation of wild-type or Bmal1-deleted microglia into the corpus callosum of NG2DsRed mice revealed that functional microglial clocks are required for effective recruitment of oligodendrocyte progenitor cells (OPCs). In contrast, microglia from neuroinflammatory brains failed to recruit OPCs, consistent with disrupted clock function and persistent activation. These findings identify microglial clocks as essential regulators of functional homeostasis and glial–glial communication and suggest that preserving circadian clock function in microglia may help mitigate neuroinflammatory damage and maintain white matter integrity.