The circadian regulation of macrophage physiology : a multi-omics approach

Abstract

Nearly all forms of life have evolved intricate and extensive mechanisms to synchronize inner physiology with predictable daily environmental changes. These mechanisms are known as circadian rhythms and are generated at the cellular level by a conserved transcription/translation feedback loop to regulate an astounding amount of cellular, tissue and organism-level processes. Chronic disruption of circadian rhythms is associated with an increased risk for disease, including metabolic, cardiovascular and neurodegenerative diseases. Because all of these diseases associated with chronic circadian disruption share underlying pathologies rooted in inflammation, we sought to further understand the mechanistic roles of circadian regulation in immunity and inflammation by focusing on the circadian regulatory networks in macrophages, a key immune cell involved in inflammation.

Utilizing cytokine paneling, we profiled the systemic immunological consequences of chronic circadian disruption and identified a diverse range of cytokines secreted by and/or targeting macrophages. We further developed robust in vitro methods for examining circadian changes in macrophages to generate two large datasets profiling the macrophage transcriptome and proteome over circadian time with unprecedented comprehensiveness for a mammalian tissue. By also developing novel computational tools to analyze our circadian omics datasets, we identified and characterized large proportions of the macrophage transcriptome and proteome regulated by macrophages’ endogenous circadian timekeeping mechanism. Our omics analysis revealed that circadian rhythms regulate fundamental cellular processes in macrophages, such as metabolism and protein turnover, to ultimately influence macrophages inflammation-related processes, including those relevant to diseases such as Alzheimer’s disease. This work provides a foundational understanding of circadian regulation of macrophages and, consequently, inflammation to ultimately inform potential approaches for prevention and treatment of disease.