Microglial clock dysfunction during neuroinflammation impairs oligodendrocyte progenitor cell recruitment and disrupts neuroimmune homeostasis.

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 -deleted microglia, as well as control or neuroinflammatory microglia, into the corpus callosum of NG2 reporter mice and evaluated oligodendrocyte progenitor cell (OPC) recruitment.

RESULTS

LPS-induced neuroinflammation triggered a phase shift in the core clock gene and disrupted the rhythmic expression of its targets, including , and , resulting in sustained microglial activation. Transplanted wild-type microglia effectively recruited OPCs, whereas both -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.