Why Lungs Keep Time: Circadian Rhythms and Lung Immunity

Abstract

Circadian rhythms are daily cycles in biological function that are ubiquitous in nature. Understood as a means for organisms to anticipate daily environmental changes, circadian rhythms are also important for orchestrating complex biological processes such as immunity. Nowhere is this more evident than in the respiratory system, where circadian rhythms in inflammatory lung disease have been appreciated since ancient times. In this focused review we examine how emerging research on circadian rhythms is being applied to the study of fundamental lung biology and respiratory disease. We begin with a general introduction to circadian rhythms and the molecular circadian clock that underpins them. We then focus on emerging data tying circadian clock function to immunologic activities within the respiratory system. We conclude by considering outstanding questions about biological timing in the lung and how a better command of chronobiology could inform our understanding of complex lung diseases.

Keywords: circadian; clock; inflammation; lung; pulmonary; rhythm.

Figure 1

Schematic depiction of the core circadian clock for mammals. Clock genes are depicted as arrows, and their protein products are represented as ovals or circles. Yellow boxes depict E-boxes or ROR-responsive elements (RREs) that are bound by BMAL1/CLOCK or REV-ERB/ROR proteins, respectively. For simplicity, we have not depicted accessory proteins such as casein kinase 1δ/ε (CK1δ/ε) that serve to adjust periodicity and phase of the clock but are not central to rhythm generation (39). Note that there are additional molecular clock constituents (also not depicted) that are expressed selectively in the central nervous system, for example, NPAS2 (a functional homologue of CLOCK) and DEC1/2 (that provide additional negative feedback to BMAL1/CLOCK) (68, 142).

Figure 2

Lung circadian gene expression is specialized for immune regulation. Depicted is a functional enrichment analysis of the human and mouse lung circadian transcriptome synthesized from recently published data (74, 80). Enriched functional enrichment terms are positioned along a 24-h time line expressed in units of zeitgeber time (ZT), where ZT0 represents the onset of daytime (yellow) and Z12 the onset of nighttime (blue). Functional enrichment terms relating to immune function are colored red. In both mice and humans, immune pathways are predominantly enriched at the gene expression level during their respective natural rest phases.

Figure 3

Schematic depicting the circadian control of homeostatic leukocyte trafficking in the lung. The diagram is synthesized from data in several recent publications detailed in this review (–110). Cell-surface markers important for rhythmic homing of leukocytes are depicted. Receptors whose cell surface expression oscillates in a circadian manner are colored purple. Also depicted are genes important for rhythms in leukocyte removal by interstitial phagocytic cells and for rhythmic homing to area lymph nodes.

Figure 4

Clock gene bmal1 regulates post-viral chronic lung disease in mice. Mice were intranasally infected with 10⁵ pfu of mouse parainfluenza virus (SeV; a–c) or 5 pfu of influenza virus [influenza A virus (IAV) strain A/WS/33 H1N1; d–f] and PAS-stained histological sections were prepared 49 days or 21 days postinfection, respectively. (a,b) SeV-infected wild-type (wt) and bmal1-knockout (ko) mouse lungs, respectively, as described in our previous report (114). (d,e) IAV-infected mice wt and bmal1-ko mouse lungs, respectively. Morphometric quantification of lung remodeling after SeV or IAV infection based on bmal1 genotype (mean ± SE) is provided in panels c and f, respectively (*p < 0.05, student’s 2-tailed t-test).