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

Science Immunology, vol. 10, pp. eadn3080

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.

Authors 18

1. Lucia Y. Du corresponding

   University of Auckland · University of Basel

   Affiliation as printed

   Allen Discovery Center for Cell Lineage Tracing, Seattle, WA, USA

   Biozentrum, University of Basel, Basel, Switzerland

   Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

2. Pramuk Keerthisinghe corresponding

   University of Auckland · University of Otago

   Affiliation as printed

   Centre For Neuroendocrinology, University of Otago, Dunedin, New Zealand

   Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

3. Leah Rolland

   University of Auckland

   Affiliation as printed

   Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

4. Yih Jian Sung

   University of Auckland

   Affiliation as printed

   Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

5. Hannah Darroch

   University of Auckland · University of Otago

   Affiliation as printed

   Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

   Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

6. Tanja Linnerz

   University of Auckland

   Affiliation as printed

   Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

7. Elina Ashimbayeva

   University of Auckland

   Affiliation as printed

   Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

8. Matthew J. Grant
   Affiliation as printed

   Auckland, New Zealand

9. Purvi M. Kakadia

   University of Auckland

   Affiliation as printed

   Leukaemia & Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

10. Anassuya Ramachandran

    University of Auckland

    Affiliation as printed

    Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

11. Alexander Tups

    University of Otago

    Affiliation as printed

    Centre For Neuroendocrinology, University of Otago, Dunedin, New Zealand

12. Herman P. Spaink Aachen Institute of Biology, Leiden University

    Leiden University

    Affiliation as printed

    Institute of Biology, Leiden University, Leiden, Netherlands

13. Stefan K. Bohlander

    University of Auckland

    Affiliation as printed

    Leukaemia & Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

14. James Frederick Cheeseman

    University of Auckland

    Affiliation as printed

    Department of Anaesthesiology, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

15. Philip S. Crosier

    University of Auckland

    Affiliation as printed

    Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

16. Jonathan W. Astin

    University of Auckland

    Affiliation as printed

    Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

17. Guy Robert Warman

    University of Auckland

    Affiliation as printed

    Department of Anaesthesiology, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

18. Christopher J. Hall corresponding

    University of Auckland

    Affiliation as printed

    Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand