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Proc Natl Acad Sci U S A. 2020 Jan 21;117(3):1543-1551. doi: 10.1073/pnas.1915932117. Epub 2020 Jan 3.

The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia.

Author information

1
Faculty of Biology, Medicine, and Health, Manchester Academic Health Sciences Centre, University of Manchester, M13 9PT Manchester, United Kingdom.
2
Manchester Foundation Trust, Manchester Academic Health Science Centre, M13 9WL Manchester, United Kingdom.
3
National Institute for Health Research, John Radcliffe Hospital, Oxford Biomedical Research Centre, OX3 9DU Oxford, United Kingdom.
4
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, OX37LE Oxford, United Kingdom.
5
Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, LS9 7TF Leeds, United Kingdom.
6
Department of Infection Medicine and Medical Research Council Centre for Inflammation Research, University of Edinburgh, EH16 4TJ Edinburgh, United Kingdom.
7
Faculty of Biology, Medicine, and Health, Manchester Academic Health Sciences Centre, University of Manchester, M13 9PT Manchester, United Kingdom; john.blaikley@manchester.ac.uk andrew.loudon@manchester.ac.uk David.Ray@ocdem.ox.ac.uk.
8
National Institute for Health Research, John Radcliffe Hospital, Oxford Biomedical Research Centre, OX3 9DU Oxford, United Kingdom; john.blaikley@manchester.ac.uk andrew.loudon@manchester.ac.uk David.Ray@ocdem.ox.ac.uk.

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.

KEYWORDS:

RhoA; Streptococcus pneumoniae; actin cytoskeleton; circadian; phagocytosis

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