Circadian Clock protein Bmal1 drives inflammatory homing in monocytes via augmented Cxcr4 and Ccr2 axis

Chronodisruption from shift work or sleep disruption is associated with inflammatory diseases, but the molecular pathways linking circadian disruption to aberrant immune cell trafficking remain unclear. Here, we identify a circadian-immune circuit wherein the core clock protein BMAL1 regulates monocyte homing by controlling chemokine receptors CXCR4 and CCR2. In sleep-disrupted individuals, we observed elevated monocyte counts alongside increased BMAL1 and chemokine receptor expression. Using a physiologically relevant murine model of chronic chronodisruption, we found that BMAL1 upregulation alters the diurnal rhythm of monocyte trafficking, leading to aberrant splenic retention and amplified chemokine-driven migratory signaling. ChIP-seq analysis revealed BMAL1 occupancy at enhancer regions of Cxcr4 and Ccr2, and its knockdown significantly attenuated their expression and associated PI3K–CDC42/RAC1 signaling. Adoptively transferred monocytes from chronodisrupted mice showed no trafficking abnormalities in healthy recipients but displayed a biased migratory preference for inflamed liver tissue upon inflammatory challenge. Our findings identify the BMAL1–chemokine axis as a regulator of monocyte trafficking and provide a mechanistic basis for heightened inflammatory responses under conditions of circadian disruption.