The following study was conducted by Scientists from University of Manchester; National Institute for Health Research, Oxford Biomedical Research Centre, Oxford; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford; University of Leeds; Medical Research Council Centre for Inflammation Research, University of Edinburgh, United Kingdom. Study is published in Proceedings of the National Academy of Sciences Journal as detailed below.
Proceedings of the National Academy of Sciences 117(3): 1543-1551
The Clock Gene Bmal1 Inhibits Macrophage Motility, Phagocytosis, and Impairs Defense Against Pneumonia
Significance
The circadian clock extensively regulates physiology, with an emerging role in immunity. Bacterial infection development, progression, and resolution depend on the time of day, but through an unknown mechanism. Here, we show that time of day regulates macrophage phagocytosis, and that the core clock protein BMAL1 is responsible. BMAL1 regulates RhoA-dependent macrophage motility and bacterial engulfment, and loss of BMAL1 enhances antibacterial immunity. We identify a genetic circuit linking BMAL1 binding to motility, cytoskeletal gene expression, and RhoA activation. With the rise in antimicrobial resistance, finding new ways to enhance immunity, by targeting clock components, offers new therapeutic opportunities.
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.
Source:
Proceedings of the National Academy of Sciences
URL: https://www.pnas.org/content/117/3/1543
Citation:
Kitchen, G. B., P. S. Cunningham, et al. (2020). “The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia.” Proceedings of the National Academy of Sciences 117(3): 1543-1551.
