Microglia coordinate circadian regulation of glymphatic brain clearance in neuroimmune disease: a conceptual framework

Abstract The glymphatic system is a brain-wide fluid and solute transport pathway that contributes to cerebrospinal fluid-interstitial fluid exchange and the removal of metabolites, inflammatory mediators, and aggregation-prone proteins. Glymphatic activity is shaped by sleep state, vascular pulsatility, respiration, vasomotion, astrocytic aquaporin-4 (AQP4) polarization, meningeal lymphatic drainage, and circadian timing. However, key aspects of brain fluid transport remain debated, including the relative roles of perivascular spaces, periarterial basement membrane pathways, intramural periarterial drainage, diffusion, convection, and anesthesia-dependent physiology. These uncertainties are central to neuroimmune disease, where inflammation, sleep disruption, vascular dysfunction, astrocytic disorganization, and microglial state changes frequently coexist. Here, we review evidence that microglia may coordinate circadian regulation of glymphatic brain clearance. Microglia are circadian, purinergic, and morphologically dynamic immune cells positioned near synapses, vessels, astrocytes, and perivascular spaces. Microglial activity appears to be temporally coupled to physiological states and clearance pathways relevant to glymphatic function: microglial surveillance varies across natural sleep-wake states, microglial phagocytosis can compensate for impaired AQP4-dependent clearance, and meningeal lymphatic drainage shapes microglial inflammatory responses. Recent work further shows that microglial morphology, signaling through the P2Y12 receptor (encoded by P2RY12), and glymphatic tracer influx are linked across Zeitgeber time, and that acute P2Y12 blockade can phase-shift glymphatic rhythms and alter sleep architecture. We propose that microglia may act as neuroimmune chronomodulators that influence the timing and spatial organization of clearance rather than as simple enhancers or inhibitors of flow; however, microglial changes may also represent adaptive responses to altered sleep, vascular physiology, astrocytic state, or glymphatic transport. In neuroimmune disease, glymphatic dysfunction may reflect temporal misalignment among microglial state, sleep architecture, vascular dynamics, astrocytic AQP4 polarity, and fluid transport routes. This framework supports temporally resolved experimental designs and translational studies integrating glymphatic imaging, sleep physiology, circadian biomarkers, inflammatory markers, vascular measures, and cognitive outcomes.