Circadian Rhythms in Immunity

Abstract

Purpose of review: This review is focused on the existing evidence for circadian control of innate and adaptive immune responses to provide a framework for evaluating the contributions of diurnal rhythms to control of infections and pathogenesis of disease.

Recent findings: Circadian rhythms driven by cell-autonomous biological clocks are central to innate and adaptive immune responses against microbial pathogens. Research during the past few years has uncovered circadian circuits governing leukocyte migration between tissues, the magnitude of mucosal inflammation, the types of cytokines produced, and the severity of immune diseases. Other studies revealed how disruption of the circadian clock impairs immune function or how microbial products alter clock machinery. Revelations concerning the widespread impact of the circadian clock on immunity and homeostasis highlight how the timing of inflammatory challenges can dictate pathological outcomes and how the timing of therapeutic interventions likely determines clinical efficacy. An improved understanding of circadian circuits controlling immune function will facilitate advances in circadian immunotherapy.

Keywords: Allergy; Asthma; Clock; Infection; Microbiota; Migration.

Figure 1.. Organization of central and cell-intrinsic peripheral oscillators.

The central oscillator is comprised of the SCN in the hypothalamus, which receives light signals and transmits rhythmic cues to the peripheral oscillators via hormone and neural pathways that are further modulated by timing of food intake and other environmental cues. The peripheral clock machinery is comprised of three interlocking feedback loops. BMAL1 and CLOCK binding to E-box elements drives transcription of multiple clock-controlled genes. As PER and CRY accumulate, they translocate back into the nucleus to repress BMAL1:CLOCK driven gene transcription, including that of PER and CRY. REV-ERBα and RORα alternatively regulate expression of RORE element associated genes, including BMAL1 and NFIL3. NFIL3 and DBP in turn alternatively regulate expression of genes like PER via D-box elements. Each element modulates expression of clock-controlled genes that may either contribute to circadian expression of other genes or have a circadian expression profile without feeding back into the molecular clock machinery.