Abstract
The circadian clock broadly governs immune cell function, leading to time-of-day differences in inflammatory responses and subsequently, pathogen clearance. However, the effect of inflammatory signals on circadian machinery is poorly understood. We found that in bone marrow-derived macrophages, some host-derived pro-inflammatory cytokines, e.g., IFN-γ or TNF-α, and pathogen-associated molecular patterns, e.g., LPS or Pam3Csk4, suppress the amplitude in oscillations of circadian negative feedback arm clock components such as PER2, and when examined, specific combinations of these immune-related signals suppressed the amplitude of these oscillations to a greater degree in both bone marrow-derived and peritoneal macrophages. At the transcript level, multiple components of the circadian clock were affected in different ways by pro-inflammatory stimulus, including Per2 and Nr1d1. This suppressive effect on PER2 did not arise from nor correlate with cell death or clock resetting. Suppression of the clock by IFN-γ was dependent on its cognate receptor; however, pharmacological inhibition of the canonical JAK/STAT and MEK pathways did not hinder suppression, suggesting a mechanism involving a non-canonical pathway. In contrast, anti-inflammatory signals such as IL-4 and dexamethasone enhanced the expression of PER2 protein and Per2 mRNA. Our results suggest that the circadian system in macrophages can differentially respond to pro- and anti-inflammatory signals in their microenvironments.
Highlights
The solar day/night cycle imposes a 24-h environment on all kingdoms of life, from prokaryotes to humans, and in response, members of all these groups of organisms have evolved ∼24-h circadian clocks that can be entrained by the environmental cycles [1]
Since IFN-γ is the main cytokine associated with classical activation in macrophages, we investigated the influence of IFN-γ and other pro-inflammatory stimuli on the macrophage clock
The ability of macrophages to be activated and polarized into different subsets has been known for several decades [48], yet little is known about how polarization affects the cell autonomous circadian clock
Summary
The solar day/night cycle imposes a 24-h environment on all kingdoms of life, from prokaryotes to humans, and in response, members of all these groups of organisms have evolved ∼24-h circadian clocks that can be entrained by the environmental cycles [1]. The master clock helps to synchronize cells in the periphery [7, 8], including monocytes and macrophages, which exhibit robust cell-autonomous circadian rhythms [2, 9,10,11,12,13,14,15,16,17,18,19,20,21]. These rhythms are entrained and affected by a range of signals and stimuli, including hormones and nutrients [22, 23]; many of the important immune signals in circadian biology are uncharacterized.
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