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Work on circadian rhythms is supported in the J.B. laboratory
by National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) grants R01DK100814 and 2R01DK090625 and in the
M.A.L. laboratory by NIDDK grant R01DK45586 and the JPB
Foundation. M.A.L. serves on advisory boards for Pfizer and
Eli Lilly and Company. J.B. has a financial interest in Reset
Therapeutics, a biotechnology company developing therapeutics
related to sleep and metabolism. We thank B. Marcheva for the
figures. We apologize that space limitations prevented citation
of all relevant literature.
Immunity around the clock
Kevin Man,1 Andrew Loudon,2 Ajay Chawla1,3*
Immunity is a high-cost, high-benefit trait that defends against pathogens and noxious
stimuli but whose overactivation can result in immunopathologies and sometimes even
death. Because many immune parameters oscillate rhythmically with the time of day, the
circadian clock has emerged as an important gatekeeper for reducing immunity-associated
costs, which, in turn, enhances organismal fitness. This is mediated by interactions between
extrinsic environmental cues and the intrinsic oscillators of immune cells, which together
optimize immune responses throughout the circadian cycle. The elucidation of these
clock-controlled immunomodulatory mechanisms might uncover new approaches for
treating infections and chronic inflammatory diseases.
Virtually all life on Earth is exposed to reg- ular 24-hour environmental cycles gener- ated by the planet’s rotation. This in turn has led to the evolution of daily (circadian) rhythms, driven by cell-autonomous biological clocks, which enable organisms to anticipate and adapt to the temporal changes in their
environment (1). The sleep-wake cycle is perhaps the most obvious output of the circadian
system, but numerous other physiological systems are under circadian control, including behavior and locomotor activity; body temperature;
the cardiovascular, digestive, and endocrine systems; and metabolic and immune functions (2–7).
In mammals, the central circadian pacemaker
is located in the suprachiasmatic nucleus (SCN),
which entrains peripheral clocks found in nearly
every cell of the body (2, 3). The SCN oscillator
has two distinct properties. First, it is the only
part of the circadian system that has retinal in-
nervation, allowing it to be entrained by the so-
lar cycle. Second, unlike the peripheral clocks,
which dampen over time, the interneuronal sig-
naling pathways that establish communication
between the SCN neurons endow it with an un-
limited capacity to generate circadian outputs.
At the organism level, circadian coherence in
peripheral tissues is maintained by rhythmic
generation of entrainment cues by the SCN, in-
cluding circadian oscillations in body temper-
ature, activity of the sympathetic nervous system
(SNS), and circulating concentrations of gluco-
corticoids. The coherence between central and
peripheral circadian clocks confers an adaptive
advantage, and its disruption has been sug-
gested to decrease organismal fitness. In support
of this, lifestyles that disrupt inherent timing
systems, such as exposure to abnormal lighting
schedules in chronic shift work, are associated
with an increased risk of cancer, metabolic dis-
orders, and cardiovascular and cerebrovascular
disease (4). Also, many human diseases exhibit
circadian rhythmicity in their pathology, includ-
ing myocardial infarction, asthma, and rheuma-
toid arthritis (4, 5).
Although diurnal variation in host immune
responses to lethal infection was demonstrated
over 50 years ago (8, 9), only recently have
studies started to uncover the multiple aspects
1Cardiovascular Research Institute, University of California,
San Francisco, CA 94143, USA. 2Faculty of Biology, Medicine
and Health, University of Manchester, Manchester, UK.
3Departments of Physiology and Medicine, University of
California, San Francisco, CA 94143, USA.
*Corresponding author. Email: firstname.lastname@example.org.
uk (A.L.); email@example.com (A.C.)
Fig. 1. Interlocking loops of the molecular clock
drive immune responses. The circadian pacemaker
is controlled by three interlocked transcription-translation feedback loops, involving rhythmic transcriptional repressors that act on D-box, E-box, and
RORE sites. Genes driving the core clockwork also
regulate multiple noncircadian pathways. Two of
the circadian oscillators, NFIL3 and RORa, also
regulate development of ILCs and TH17 cells. Lines
terminating in perpendicular bars denote inhibition.
DBP, albumin D-box binding protein; CRYs, cryptochromes; PERs, Periods.