The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia
| Autor: | John Blaikley, Gareth B. Kitchen, Tracy Hussell, Mudassar Iqbal, Robert Maidstone, Laura Matthews, Hannah J. Durrington, Peter S. Cunningham, James Bagnall, Nicola Begley, Matthew Baxter, Ben Saer, Toryn Poolman, Julie E. Gibbs, Andrew S. I. Loudon, David W. Ray, David H. Dockrell |
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| Rok vydání: | 2020 |
| Předmět: |
endocrine system
actin cytoskeleton RHOA Disease Resistance/genetics Circadian Clocks/genetics Lydia Becker Institute Phagocytosis/drug effects Phagocytosis Motility Cell Movement/drug effects Cell morphology Mice 03 medical and health sciences Macrophages/drug effects 0302 clinical medicine ResearchInstitutes_Networks_Beacons/lydia_becker_institute_of_immunology_and_inflammation rhoA GTP-Binding Protein/metabolism Animals Macrophage Cytoskeleton Actin ARNTL Transcription Factors/antagonists & inhibitors 030304 developmental biology Mice Knockout 0303 health sciences Multidisciplinary biology Circadian RhoA Pneumonia Pneumococcal/metabolism Streptococcus pneumoniae/pathogenicity Actin cytoskeleton 3. Good health Cell biology Mice Inbred C57BL Disease Models Animal Streptococcus pneumoniae Actins/metabolism biology.protein Female 030217 neurology & neurosurgery |
| Zdroj: | Kitchen, G B, Cunningham, P S, Poolman, T M, Iqbal, M, Maidstone, R, Baxter, M, Bagnall, J, Begley, N, Saer, B, Hussell, T, Matthews, L C, Dockrell, D H, Durrington, H J, Gibbs, J E, Blaikley, J F, Loudon, A S & Ray, D W 2020, ' The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia ', Proceedings of the National Academy of Sciences, vol. 117, no. 3, pp. 1543-1551 . https://doi.org/10.1073/pnas.1915932117 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1915932117 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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