Immunity's fourth dimension: approaching the circadian-immune connection

Abstract

The circadian system ensures the generation and maintenance of self-sustained ~24-h rhythms in physiology that are linked to internal and environmental changes. In mammals, daily variations in light intensity and other cues are integrated by a hypothalamic master clock that conveys circadian information to peripheral molecular clocks that orchestrate physiology. Multiple immune parameters also vary throughout the day and disruption of circadian homeostasis is associated with immune-related disease. Here, we discuss the molecular links between the circadian and immune systems and examine their outputs and disease implications. Understanding the mechanisms that underlie circadian-immune crosstalk may prove valuable for devising novel prophylactic and therapeutic interventions.

Figure 1. A model depicting the circadian immune connection

Systemic circadian cues circadian immune outputs can be generated both directly and indirectly . Circadian clock proteins such as CLOCK and BMAL1 bind promoter E-box elements and ROREs to positively regulate expression of clock-controlled genes (CCGs). Several CCGs (e.g. Per2) have been linked to control of immune cell function and immune-related genes might also be under control of clock proteins (immune CCGs, e.g. TLR9). Clock controlled PER and CRY proteins inhibit CLOCK:BMAL1-mediated activation of CCGs by, whereas clock controlled REV-ERBα proteins negatively regulate BMAL1 gene expression. These pathways create a negative feedback look. REV-ERBα proteins have also been implicated in negative control of cytokine gene expression. Daily systemic cues transmitted by the neuroendocrine system might also generate circadian immune outputs by modulating of immune gene expression and signaling or through the entrainment of molecular clock mechanisms. Circadian immune outputs underlie daily variations in immune-mediated disease susceptibility symptoms and treatment efficacy. Immune factors, for example proinflammatory cytokines, can also feedback to the circadian system, either by modulating the circadian molecular clock or the neural and humoral mechanisms that conveying systemic circadian information. Hourglasses depict rhythmic expression of clock genes and CCGs, while the clocks depict oscillations outside the core molecular clockwork.