| Title: |
A light-regulated circadian timer optimizes neutrophil bactericidal activity to boost daytime immunity. |
| Authors: |
Du, Lucia Yi; Keerthisinghe, Pramuk; Rolland, Leah; Sung, Yih Jian; Darroch, Hannah; Linnerz, Tanja; Ashimbayeva, Elina; Grant, Matthew J.; Kakadia, Purvi M.; Ramachandran, Annasuya; Tups, Alexander; Spaink, Herman P.; Bohlander, Stefan K.; Cheeseman, James; Crosier, Philip S.; Astin, Jonathan W.; Warman, Guy; Hall, Christopher J. |
| Source: |
Science Immunology; 2025, Vol. 10 Issue 107, p1-19, 19p |
| Subject Terms: |
GENE expression; CLOCK genes; REACTIVE oxygen species; IMMUNE response; GENETIC transcription regulation; CIS-regulatory elements (Genetics) |
| Abstract: |
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. Per2 was required in neutrophils for reactive oxygen species (ROS) production and bacterial killing by enhancing infection-responsive expression of high-mobility group box 1a (hmgb1a). 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 hmgb1a expression. A conserved cis-regulatory element with BMAL1 and nuclear factor κB binding motifs gated infection-responsive hmgb1a expression to the light phase. Mutagenesis of the BMAL1 motif in neutrophils blunted the priming effect of light on bactericidal activity and hmgb1a expression. These findings identify a light-responsive cell-intrinsic timer that controls time-of-day variations in antibacterial activity. Editor's summary: Host responses to bacterial infection are influenced by circadian rhythms. Neutrophils play a key role in antibacterial immunity, yet how the neutrophil circadian clock is regulated is not well understood. Using a zebrafish model of bacterial infection, Du et al. identified that the core clock component Per2 was elevated in neutrophils under constant light conditions and was required for bactericidal function and host survival. During the light phase, Per2 positively regulated expression of the infection-responsive gene hmgb1a by interacting with a cis-regulatory element containing BMAL1 and nuclear factor κB binding motifs, resulting in enhanced bactericidal activity. Thus, transcriptional regulation of neutrophil function is influenced by the circadian clock, which enhances immunity during periods of activity. —Hannah Isles [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |