Susceptibility rhythm to bacterial endotoxin in myeloid clock-knockout mice

Elife. 2021 Oct 18:10:e62469. doi: 10.7554/eLife.62469.


Local circadian clocks are active in most cells of our body. However, their impact on circadian physiology is still under debate. Mortality by endotoxic (LPS) shock is highly time-of-day dependent and local circadian immune function such as the cytokine burst after LPS challenge has been assumed to be causal for the large differences in survival. Here, we investigate the roles of light and myeloid clocks on mortality by endotoxic shock. Strikingly, mice in constant darkness (DD) show a threefold increased susceptibility to LPS as compared to mice in light-dark conditions. Mortality by endotoxic shock as a function of circadian time is independent of light-dark cycles as well as myeloid CLOCK or BMAL1 as demonstrated in conditional knockout mice. Unexpectedly, despite the lack of a myeloid clock these mice still show rhythmic patterns of pro- and anti-inflammatory cytokines such as TNFα, MCP-1, IL-18, and IL-10 in peripheral blood as well as time-of-day and site-dependent traffic of myeloid cells. We speculate that systemic time-cues are sufficient to orchestrate innate immune response to LPS by driving immune functions such as cell trafficking and cytokine expression.

Keywords: circadian rhythm; immunology; inflammation; macrophages; mouse; sepsis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics*
  • ARNTL Transcription Factors / metabolism
  • Animals
  • CLOCK Proteins / genetics*
  • CLOCK Proteins / metabolism
  • Circadian Clocks / genetics*
  • Circadian Rhythm / genetics*
  • Male
  • Mice
  • Mice, Knockout


  • ARNTL Transcription Factors
  • Bmal1 protein, mouse
  • CLOCK Proteins
  • Clock protein, mouse

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.