Susceptibility rhythm to bacterial endotoxin in myeloid clock-knockout mice

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Abstract

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 three-fold 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 TNF,α MCP-1, IL-18 and IL-10 in peripheral blood as well as time-of-day and site dependent traffc 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 traffcking and cytokine expression.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Veronika Lang

Laboratory of Chronobiology, Charite Universitaetsmedizin Berlin, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Sebastian Ferencik

Laboratory of Chronobiology, Charite Universitaetsmedizin Berlin, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Bharath Ananthasubramaniam

Humboldt Universitaet zu Berlin, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4467-1546
Achim Kramer

Laboratory of Chronobiology, Charite Universitaetsmedizin Berlin, Berlin, Germany

Competing interests
The authors declare that no competing interests exist.
Bert Maier

Laboratory of Chronobiology, Charite Universitaetsmedizin Berlin, Berlin, Germany

For correspondence
bert.maier@charite.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5254-008X

Funding

Deutsche Forschungsgemeinschaft (MA 5108/1-1)

Bert Maier

Deutsche Forschungsgemeinschaft (AN 1553-2/1)

Bharath Ananthasubramaniam

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

Ethics

Animal experimentation: All procedures were authorized by and performed in strict accordance with the guidelines and regulations of the German animal protection law (Deutsches Tierschutzgesetz). The protocols were approved by the ethics comittee of the Landesamt für Gesundheit und Soziales (LaGeSo, Permit Number G 0161/12 and G0211/14).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.