Immunity around the clock

Abstract

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.

Figure 1. Interlocking loops of the molecular clock drive immune responses

The circadian pacemaker is controlled by 3 inter-locked transcription/translation feedback loops, involving rhythmic transcriptional repressors that act on E-Box, RORE, and D-Box sites. Genes driving the core clockwork also regulate multiple other non-circadian pathways. Two of the circadian oscillators, NFIL3 and RORα, also regulate development of ILCs and Th17 cells.

Figure 2. Gating of immune responses by the circadian clock

(A) Cost-benefit trade-offs of immunity. The circadian clock functions to minimize the costs (direct costs and vulnerabilities) and maximize benefits of immunity. Loss of the circadian clock increases the costs of immunity for a given level of benefit. Disrupted clock is depicted in red, whereas normal clock is shown in blue. (B) The circadian clock temporally gates various arms of the innate immune response. Peaks of innate immune parameters are plotted on a curve depicting the oscillation of Bmal1 mRNA during a circadian cycle. Zeitgeber time (ZT). ZT0 is the start of the light phase and ZT12 is the beginning of the dark phase, during a 24-hour light-dark cycle. (C) Temporal gating of inflammatory responses by the circadian clock. The curve depicts the rhythmic changes in an inflammatory parameter, such as production of cytokines or chemokines, or trafficking of immune cells. The cellular clock generates the nadirs in this inflammatory parameter and its loss is associated with derepression of the nadirs without significant change in the peak, which increase the duration of inflammation. Disrupted clock is depicted in red, whereas normal clock is shown in blue.

Figure 3. Cell-extrinsic and -intrinsic generation of oscillatory immune responses

(A) Rhythmic oscillations in entrainment cues regulate homeostatic trafficking of hematopoietic stem cells and leukocytes. The SNS is the central entrainment cue that controls expression of chemokines and adhesion molecules in stromal cells, such as bone marrow stromal cells and endothelial cells, which imparts rhythmicity to trafficking of hematopoietic stem cells and leukocytes. (B) Cell-intrinsic clocks regulate basal and inducible programs in myeloid cells for maintenance of local homeostasis.

Figure 4. Models for anti-inflammatory actions of clock in myeloid cells

(A) Rhythmic gating of basal genes. Interactions between CLOCK/BMAL1 heterodimers and the polycomb repressor complex 2 (PRC2) results in rhythmic repression of chemokine genes (such as Ccl2). (B–D). Rhythmic gating of inducible genes. Several modes of action are proposed for rhythmic gating of LPS-induced inflammatory genes. The CLOCK protein can acetylate p65 subunit of NF-κB to induce expression of TNF, and its rhythmic sequestration by BMAL1 can drive oscillations in TNF expression (B). Recruitment of REV-ERB repressor complexes to inflammatory genes, such as Il6, can rhythmically repress their expression (C). Glucocorticoid- receptor mediated repressive effects on inflammatory chemokines requires a functional cellular clock, which may be essential for recruitment of glucocorticoid receptor (GR) complexes to glucocorticoid binding site (GBS) on the Cxcl5 gene (D).