Immunometabolism around the Clock

Carroll, Richard G.; Timmons, George A.; Cervantes-Silva, Mariana P.; Kennedy, Oran D.; Curtis, Annie M.

doi:10.1016/j.molmed.2019.04.013

Cited by 52 publications

(37 citation statements)

References 124 publications

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“…In summary, our findings reveal a paradigm where post-transcriptional circadian regulation times naïve macrophages during the inactive, rest phase to be metabolically primed to resemble an anti-inflammatory phenotype (Figure 7), which characteristically has intact, robust ATP production via mitochondrial oxidative phosphorylation. Upon entering the active phase, the immunometabolic state resembles a pro-inflammatory programming, as reliance on glycolysis over oxidative phosphorylation is a hallmark of pro-inflammatory macrophages (Van den Bossche, O'Neill and Menon, 2017;Carroll et al, 2019). A circadianly-timed proclivity for inflammatory responses in the active phase was consistent with our findings that zymosan is more readily phagocytized at the end of the active phase ( Figure 6C) as well as the majority of studies in both humans and nocturnal animals, which show that immune challenges are generally less effectively neutralized when exposed during the inactive phase or under circumstances of circadian disruption when macrophages are not primed for appropriate inflammatory responses (Geiger, Fagundes and Siegel, 2015;Nagy and Haschemi, 2015;Van den Bossche, O'Neill and Menon, 2017).…”

Section: Discussionmentioning

confidence: 99%

Post-Transcriptional Circadian Regulation in Macrophages Organizes Temporally Distinct Immunometabolic States

Collins

Cervantes-Silva

Timmons

et al. 2020

Preprint

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Our core timekeeping mechanism, the circadian clock, regulates an astonishing amount of cellular physiology and behavior, playing a vital role in organismal fitness. While the mechanics of circadian control over cellular regulation can in part be explained by the transcriptional activation stemming from the positive arm of the clock's transcription-translation negative feedback loop, research has shown that extensive circadian regulation occurs beyond transcriptional activation in fungal species and data suggest that this post-transcriptional regulation may also be preserved in mammals. To determine the extent to which circadian output is regulated post-transcriptionally in mammalian cells, we comprehensively profiled the transcriptome and proteome of murine bone marrow-derived macrophages in a high resolution, sample rich time course. We found that only 15% of the circadian proteome had corresponding oscillating mRNA and this regulation was cell intrinsic. Ontological analysis of oscillating proteins revealed robust temporal enrichment for protein degradation and translation, providing potential insights into the source of this extensive posttranscriptional regulation. We noted post-transcriptional temporal-gating across a number of connected metabolic pathways. This temporal metabolic regulation further corresponded with rhythms we observed in ATP production, mitochondrial morphology, and phagocytosis. With the strong interconnection between cellular metabolic states and macrophage phenotypes/responses, our work demonstrates that post-transcriptional circadian regulation in macrophages is broadly utilized as a tool to confer time-dependent immune function and responses. As macrophages coordinate many immunological and inflammatory functions, an understanding of this regulation provides a framework to determine the impact of circadian regulation on a wide array of disease pathologies.

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Section: Discussionmentioning

confidence: 99%

Post-Transcriptional Circadian Regulation in Macrophages Organizes Temporally Distinct Immunometabolic States

Collins

Cervantes-Silva

Timmons

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…On the face of it, a comparison of pre-and post-exercise serum may seem like a reasonable study design, but it means that the anti-oncogenic effects cannot be specifically attributed to exercise alone. Indeed, the serum profile may be subject to circadian fluctuation over time (Carroll et al 2019), and repeated venous blood sampling (used in some studies) may result in physiological changes that could also have anti-tumorigenic effects, for example an increase in circulating adrenaline (Carruthers et al 1970). Indeed, plasma cytokines have been shown to increase from pre-to post-acute aerobic exercise, but this increase was similar in magnitude and not statistically different from a time-matched control condition (Windsor et al 2018).…”

Section: Effects Of Acute Exercisementioning

confidence: 99%

Anti-carcinogenic effects of exercise-conditioned human serum: evidence, relevance and opportunities

et al. 2021

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Regular physical activity reduces the risk of several site-specific cancers in humans and suppresses tumour growth in animal models. The mechanisms through which exercise reduces tumour growth remain incompletely understood, but an intriguing and accumulating body of evidence suggests that the incubation of cancer cells with post-exercise serum can have powerful effects on key hallmarks of cancer cell behaviour in vitro. This suggests that exercise can impact tumour biology through direct changes in circulating proteins, RNA molecules and metabolites. Here, we provide a comprehensive narrative overview of what is known about the effects of exercise-conditioned sera on in vitro cancer cell behaviour. In doing so, we consider the key limitations of the current body of literature, both from the perspective of exercise physiology and cancer biology, and we discuss the potential in vivo physiological relevance of these findings. We propose key opportunities for future research in an area that has the potential to identify key anti-oncogenic protein targets and optimise physical activity recommendations for cancer prevention, treatment and survivorship.

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“…BMAL1 is linked to mitochondrial function and metabolic pathways, which influences the phenotype and activity of immune cells. Rhythmicity of immunometabolism has become a key aspect of immune defense and disease outcomes (Early and Curtis, 2016; Carroll et al, 2019). These studies illustrate how the circadian clock regulates the immune response that impacts viral replication.…”

Section: Circadian Pathways Shape Viral Infectionmentioning

confidence: 99%

The Circadian Clock and Viral Infections

2020

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The circadian clock controls several aspects of mammalian physiology and orchestrates the daily oscillations of biological processes and behavior. Our circadian rhythms are driven by an endogenous central clock in the brain that synchronizes with clocks in peripheral tissues, thereby regulating our immune system and the severity of infections. These rhythms affect the pharmacokinetics and efficacy of therapeutic agents and vaccines. The core circadian regulatory circuits and clock-regulated host pathways provide fertile ground to identify novel antiviral therapies. An increased understanding of the role circadian systems play in regulating virus infection and the host response to the virus will inform our clinical management of these diseases. This review provides an overview of the experimental and clinical evidence reporting on the interplay between the circadian clock and viral infections, highlighting the importance of virus-clock research.

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Immunometabolism around the Clock

Cited by 52 publications

References 124 publications

Post-Transcriptional Circadian Regulation in Macrophages Organizes Temporally Distinct Immunometabolic States

Post-Transcriptional Circadian Regulation in Macrophages Organizes Temporally Distinct Immunometabolic States

Anti-carcinogenic effects of exercise-conditioned human serum: evidence, relevance and opportunities

The Circadian Clock and Viral Infections

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