A light-regulated circadian timer optimizes neutrophil bactericidal activity to boost daytime immunity

The immune response exhibits strong circadian rhythmicity, with enhanced bacterial clearance often synchronized with an organism's active phase. Despite providing the bulk of cellular antibacterial defense, the neutrophil clockwork is poorly understood. Here, we used larval zebrafish to explore the role of clock genes in neutrophils during infection. <i>Per2</i> was required in neutrophils for reactive oxygen species (ROS) production and bacterial killing by enhancing infection-responsive expression of <i>high-mobility group box 1a</i> (<i>hmgb1a</i>). The Cry binding domain of Per2 was required for regulation of neutrophil bactericidal activity, and neutrophils lacking Cry1a had elevated bactericidal activity and infection-responsive <i>hmgb1a</i> expression. A conserved cis-regulatory element with BMAL1 and nuclear factor κB binding motifs gated infection-responsive <i>hmgb1a</i> expression to the light phase. Mutagenesis of the BMAL1 motif in neutrophils blunted the priming effect of light on bactericidal activity and <i>hmgb1a</i> expression. These findings identify a light-responsive cell-intrinsic timer that controls time-of-day variations in antibacterial activity.