Kitchen, GB;
Cunningham, PS;
Poolman, TM;
Iqbal, M;
Maidstone, R;
Baxter, M;
Bagnall, J;
... Ray, DW; + view all
(2020)
The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia.
Proceedings of the National Academy of Sciences of the United States of America
, 117
(3)
pp. 1543-1551.
10.1073/pnas.1915932117.
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Abstract
The circadian clock regulates many aspects of immunity. Bacterial infections are affected by time of day, but the mechanisms involved remain undefined. Here we show that loss of the core clock protein BMAL1 in macrophages confers protection against pneumococcal pneumonia. Infected mice show both reduced weight loss and lower bacterial burden in circulating blood. In vivo studies of macrophage phagocytosis reveal increased bacterial ingestion following Bmal1 deletion, which was also seen in vitro. BMAL1-/- macrophages exhibited marked differences in actin cytoskeletal organization, a phosphoproteome enriched for cytoskeletal changes, with reduced phosphocofilin and increased active RhoA. Further analysis of the BMAL1-/- macrophages identified altered cell morphology and increased motility. Mechanistically, BMAL1 regulated a network of cell movement genes, 148 of which were within 100 kb of high-confidence BMAL1 binding sites. Links to RhoA function were identified, with 29 genes impacting RhoA expression or activation. RhoA inhibition restored the phagocytic phenotype to that seen in control macrophages. In summary, we identify a surprising gain of antibacterial function due to loss of BMAL1 in macrophages, associated with a RhoA-dependent cytoskeletal change, an increase in cell motility, and gain of phagocytic function.
| Type: | Article |
|---|---|
| Title: | The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1073/pnas.1915932117 |
| Publisher version: | https://doi.org/10.1073/pnas.1915932117 |
| Language: | English |
| Additional information: | Copyright © 2020 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | circadian, Streptococcus pneumoniae, phagocytosis, sactin cytoskeleton, RhoA |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10103180 |
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