Perfect timing: circadian rhythms, sleep, and immunity - an NIH workshop summary

Abstract

Recent discoveries demonstrate a critical role for circadian rhythms and sleep in immune system homeostasis. Both innate and adaptive immune responses - ranging from leukocyte mobilization, trafficking, and chemotaxis to cytokine release and T cell differentiation -are mediated in a time of day-dependent manner. The National Institutes of Health (NIH) recently sponsored an interdisciplinary workshop, "Sleep Insufficiency, Circadian Misalignment, and the Immune Response," to highlight new research linking sleep and circadian biology to immune function and to identify areas of high translational potential. This Review summarizes topics discussed and highlights immediate opportunities for delineating clinically relevant connections among biological rhythms, sleep, and immune regulation.

Figure 1. Citations in chronotherapy and circadian research are on the rise.

(A) Number of 1990–2018 publications found with PubMed searches for “circadian” and “chronotherapy.” (B) Number of 1990–2018 publications found with PubMed searches for “sleep and immunity,” “circadian and immunity,” and “chronotherapy and immunity.” Chronotherapy is classically defined as the use of circadian information to maximize the therapeutic index of a medical intervention or to limit the amount of drug needed to achieve a clinical end point by giving it at the optimal time of day. An emerging use of the term is for the direct targeting of clock gene function to achieve a clinical end point, such as tumor killing (148). Illustrated by Rachel Davidowitz.

Figure 2. Circadian regulation in mammals.

Schematic depicting the currently accepted hierarchal model for circadian rhythm generation. Light information is conveyed by the optic nerve to the SCN, a region of the ventral hypothalamus. There, light entrains clocks within SCN neurons, and this is ultimately converted by the CNS into pulsatile chemical and neurological cues, which entrain cell-autonomous circadian clocks residing in peripheral cells. These peripheral clocks impart circadian patterns on gene expression and overall cellular physiology. For simplicity, only the core molecular clock circuitry is depicted, with positive regulatory proteins labeled green and negative regulators labeled red. However, there are many accessory proteins and metabolic pathways that can adjust the periodicity and phase of the clock but are not central to rhythm generation (for example, casein kinase 1δ/ε [ref. 23], AMPK [ref. 149], mTOR [ref. 150], p53 [ref. 151], and SIRT1 [ref. 152]). There are additional molecular clock constituents (not depicted) that in the basal state appear to have more prominent roles in CNS clocks than clocks in peripheral cells. For example, NPAS2 (a functional homolog of CLOCK) and DEC1/2 provide additional negative feedback to BMAL1/CLOCK (16, 153). Yellow boxes represent E-boxes or ROR-responsive elements (RREs), which are the promoter motifs recognized by BMAL1/CLOCK or REV-ERB/ROR proteins, respectively. Clock genes and clock-controlled genes (CGs) are represented by green and purple arrows, respectively. Illustrated by Rachel Davidowitz.

Figure 3. Multilayered circadian control of leukocyte trafficking.

Schematic depiction of the circadian regulation of specific leukocyte trafficking steps (–57, 68). These include the egress of leukocytes from the bone marrow; adhesion of circulating leukocytes to endothelial cells in the capillary beds of end organs; and removal of leukocytes from the parenchyma of organs by phagocytosis or by migration to area lymph nodes. Proteins generally important for rhythmic leukocyte trafficking at specific steps in the process are depicted in red. For a comprehensive treatment of cell-specific determinants of leukocyte trafficking rhythms, see Pick et al. (154). Lymph/Mac, lymphocyte/macrophage. Illustrated by Rachel Davidowitz.