Circadian metabolism regulates the macrophage inflammatory response

Abstract

Macrophages are an integral part of the innate immune system and coordinate host defense to microbial infections, as well as shaping the remodeling response after tissue injury. Metabolism is now appreciated to be a powerful and pervasive regulator of the identity and function of macrophages. Upon exposure to microbial ligands, macrophage inflammatory activation and the associated induction of phagocytosis, inflammatory responses, and other host defense activities are supported by dynamic changes to cellular metabolism. Of note, metabolic activity is robustly regulated in a circadian fashion, with many metabolic processes displaying peak activity in one phase of the circadian cycle and trough activity in an antiphase manner. Here, we review recent findings suggesting that circadian metabolism influences macrophage activities and particularly the inflammatory response. First, we summarize macrophage activities known to display time-of-day-dependent variation and their mechanistic basis. Second, we review metabolic processes that have been shown to be rhythmically regulated in macrophages and discuss how such circadian metabolism affects or is likely to affect macrophage activities. Third, we discuss the concept of entrainment of the macrophage clock, and consider how loss of rhythmic regulation of macrophage activities may contribute to pathophysiological conditions like shift work, obesity, and aging. Finally, we propose that circadian metabolism can be used to understand the rationale and mechanistic basis of dynamic regulation of inflammatory responses during infection.

Keywords: circadian immunometabolism; circadian metabolism; circadian rhythm; immunometabolism; macrophage inflammatory responses; macrophage metabolism.

Figure 1

Circadian rhythmicity is established by a molecular clock machinery that consists of several transcriptional complexes whose activities are interlocked in multiple transcriptional-translational feedback loops. A transcriptional heterodimeric complex comprised of BMAL and CLOCK binds to E-boxes in the genes encoding PER and CRY, while the PER-CRY heterodimer competes with BMAL-CLOCK for E-box binding to repress their own genes and eventually initiate a new round of BMAL-CLOCK activity. A second regulatory loop is mediated by BMAL-Clock induction of the genes encoding REV-ERB and ROR, which bind to RORE elements to repress or induce expression of Bmal1. The molecular clock machinery also binds to regulatory elements in so-called CCGs, and in macrophages (shown here), and this allows for diurnal rhythms in genes regulating metabolism and immunity (e.g. Klf4, Tlr9, Rela, and Nlrp3).

Figure 2

Entrainment signals “set” clock rhythms. Light entrains the central clock in the SCN, which in turn synchronizes peripheral clocks to allow all clocks in the body to “run at the same time”. Although poorly defined, entrainment signals for peripheral clocks are thought to be tissue specific and to include signals emanating from the central clock (hormonal signals and autonomic innervation), as well as feeding-related signals, body temperature, tissue hypoxia, and/or other signals. Microbial components and other signals that drive inflammatory macrophage activation are dominant over steady-state entrainment signals, impinging on the macrophage clock machinery to “reset” its rhythm so that macrophage activities can be prioritized for host defense.

Figure 3

Diurnal oscillations in metabolism influence time-of-day–dependent variation in inflammatory responses and other macrophage activities. In nocturnal mice, the active cycle spans ZT12 to ZT0/24, while the inactive cycle spans ZT0 to ZT12. Rhythmicity in metabolism is highlighted by the prevalence of catabolic metabolism in the inactive cycle and of anabolic metabolism in the active cycle. Inflammatory responses, phagocytosis, and monocyte entry into tissues peak in the active phase, compared to the inactive phase. Citations of the relevant references are indicated in brackets. “+” and “+++” denote relative levels of metabolites and/or relative degrees of activity of various metabolic processes.