File(s) under embargo

17

day(s)

until file(s) become available

Post-transcriptional circadian regulation in macrophages organizes temporally distinct immunometabolic states

journal contribution
posted on 24.05.2021, 10:56 by Emily J Collins, Mariana Patricia Cervantes Silva, George Timmons, James O'Siorain, Annie Curtis, Jennifer M Hurley
Our core timekeeping mechanism, the circadian clock, plays a vital role in immunity. Although the mechanics of circadian control over the immune response is generally explained by transcriptional activation or repression derived from this clock's transcription-translation negative-feedback loop, research suggests that some regulation occurs beyond transcriptional activity. We comprehensively profiled the transcriptome and proteome of murine bone marrow-derived macrophages and found that only 15% of the circadian proteome had corresponding oscillating mRNA, suggesting post-transcriptional regulation influences macrophage clock regulatory output to a greater extent than any other tissue previously profiled. This regulation may be explained by the robust temporal enrichment we identified for proteins involved in degradation and translation. Extensive post-transcriptional temporal-gating of metabolic pathways was also observed and further corresponded with daily variations in ATP production, mitochondrial morphology, and phagocytosis. The disruption of this circadian post-transcriptional metabolic regulation impaired immune functionality. Our results demonstrate that cell-intrinsic post-transcriptional regulation is a primary driver of circadian output in macrophages and that this regulation, particularly of metabolic pathways, plays an important role in determining their response to immune stimuli.

Funding

Molecular Clock control of the pro-inflammatory cytokine IL-1B. A Mechanistic Link between Circadian Disruption and Cardiovascular Disease | Funder: Irish Research Council (IRC) | Grant ID: IRCLA/2017/110

MacroCLOCK - Circadian Control of Macrophage Mitochondria: A New Approach in the treatment of Chronic Inflammatory Disease | Funder: Science Foundation Ireland (SFI) | Grant ID: 17/CDA/4688

A New Dimension to the Immune Response: Biological Molecular Clocks Controlling Inflammation. | Funder: Science Foundation Ireland (SFI) | Grant ID: 13/SIRG/2130(T)

Programming macrophages to suppress inflammation and promote healing after knee injury. A novel microparticle based therapeutic strategy against Post-Traumatic Osteoarthritis. | Funder: Irish Research Council (IRC) | Grant ID: 2018 2752

Impact of circadian control in mitochondrial metabolism in Dendritic Cells and their implications in vaccination. | Funder: The National Council of Science and Technology (CONACYT | Grant ID: The National Council of Science and Technology (CONACYT

National Institutes of Health, National Institute of General Medical Sciences (T32GM067545) (GM128687)

Rensselaer start up funds

Consejo Nacional de Ciencia y Tecnologia (CVU440823)

History

Associated research data files

All raw and processed sequencing data generated in this study have been submitted to the NCBI Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE157878. The mass spectrometry proteomics data generated in this study have been submitted to ProteomeXchange (http://www.proteomexchange.org) under accession number PXD022260

Comments

The original article is available at https://genome.cshlp.org

Published Citation

Collins EJ, Cervantes-Silva MP, Timmons GA, O'Siorain JR, Curtis AM, Hurley JM. Post-transcriptional circadian regulation in macrophages organizes temporally distinct immunometabolic states. Genome Research. 2021;31(2):171–85.

Publication Date

12 January 2021

PubMed ID

33436377

Department/Unit

  • RCSI Tissue Engineering Group (TERG)
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Health Professions Education
  • Vascular Biology
  • Biomaterials and Regenerative Medicine
  • Immunity, Infection and Inflammation

Publisher

Cold Spring Harbor Laboratory

Version

  • Published Version (Version of Record)