Circadian Effects on Vascular Immunopathologies

Abstract

Circadian rhythms exert a profound impact on most aspects of mammalian physiology, including the immune and cardiovascular systems. Leukocytes engage in time-of-day-dependent interactions with the vasculature, facilitating the emigration to and the immune surveillance of tissues. This review provides an overview of circadian control of immune-vascular interactions in both the steady state and cardiovascular diseases such as atherosclerosis and infarction. Circadian rhythms impact both the immune and vascular facets of these interactions, primarily through the regulation of chemoattractant and adhesion molecules on immune and endothelial cells. Misaligned light conditions disrupt this rhythm, generally exacerbating atherosclerosis and infarction. In cardiovascular diseases, distinct circadian clock genes, while functioning as part of an integrated circadian system, can have proinflammatory or anti-inflammatory effects on these immune-vascular interactions. Here, we discuss the mechanisms and relevance of circadian rhythms in vascular immunopathologies.

Keywords: atherosclerosis; circadian rhythm; endothelial cells; infarction; leukocytes.

Figure 1.

Circadian rhythms control immune-vascular interactions at steady state. Leukocytes emigrate from the blood to tissues in a rhythmic manner due to the oscillatory expression of adhesion molecules and chemokine receptors involved in the leukocyte adhesion cascade. This oscillatory expression is observed in both endothelial cells (ECs) and lymphatic ECs (LECs) of various organs, as well as in blood leukocyte subsets. A, Lineage-specific ablation of Bmal1 in ECs (Cdh5^creERT2:Bmal1^flox) or leukocyte subsets such as B cells (Cd19^creBmal1^flox) and myeloid cells (Lyz2^cre:Bmal1^flox) leads to the abrogation of rhythmic of leukocyte migration to different organs. This rhythmic recruitment of leukocyte subsets to tissues is governed by promigratory factors on both ECs and leukocytes. B, Rhythmic expression of TNF (tumor necrosis factor) in the draining lymph node (LN) enhances BMAL1-controlled ICAM (intercellular adhesion molecule)-1 expression in high endothelial venules (HEVs) in an inflammatory scenario, resulting in increased dendritic cells (DCs) homing and lymphocyte infiltration to the draining LN. Lineage-specific ablation of Bmal1 in ECs (Cdh5^creERT2:Bmal1^flox) abrogates these rhythms. C, Migration of mouse DCs into afferent lymphatic vessels of the skin follows a rhythmic pattern, peaking around Zeitgeber time (ZT) 7. This rhythmic migration is driven by the diurnal expression of adhesion molecules and chemokine-chemokine receptors on LECs and DCs. Lineage-specific ablation of Bmal1 in conventional DCs (Clec9a^cre:Bmal1^flox), LECs (Prox1^creERT2:Bmal1^flox), or ECs (Cdh5^creERT2:Bmal1^flox) abrogates these rhythms.

Figure 2.

Circadian rhythms control immune-vascular interactions in atherosclerosis and myocardial infarction (MI). Monocytes (Mo) and neutrophils (Nφ) adhere to arteries and infiltrate into the heart in a time-of-day–dependent manner, which dictates the circadian outcome of atherosclerosis and MI. Disruption of circadian rhythms generally exacerbates the disease phenotype. A, Circadian rhythm disruption, such as by misaligned light, increases atherosclerotic lesions and elevates their Icam1 and CCL2 levels. Peritoneal macrophages (Mac) from circadian-disrupted mice are more inflammatory and more likely to form foam cells in response to oxLDL (oxidized low-density lipoprotein). B, In the early stages of atherosclerosis, arteries show higher levels of CCL2 on the endothelial surface at Zeitgeber time (ZT) 1 compared with ZT13, leading to greater monocyte and neutrophil adhesion at ZT1. C, In MI models induced by left anterior descending coronary artery occlusion, MI damage is more severe at ZT13 compared with ZT5 or wake-sleep transition. Higher levels of adhesion molecules and chemokines are present at ZT13, leading to increased monocyte and neutrophil infiltration to the heart. The blockade of this infiltration by the CCR2 inhibitor RS504393, the CXCR2 inhibitor SB225002, or the depletion of neutrophils by anti-Ly6G antibodies protects the heart from severe MI damage at ZT13. D, Circadian rhythm disruption by shift work or by surgical lesion of the suprachiasmatic nucleus (SCN) has the opposite effects on MI damage. Post-MI shift work increases cardiac inflammation and macrophage infiltration and suppresses new coronary blood vessel formation and associated infarct healing. Prior-MI shift work increases cardiac inflammation and neutrophil infiltration by suppressing Nr1d1 expression. However, SCN lesion promotes blood vessel recovery and associated blood flow and cardiac anti-inflammatory CD206⁺ macrophage infiltration, which is mediated by IGF2 (insulin-like growth factor 2) and could be suppressed by an anti-IGF2R antibody. CCL2 indicates C-C motif chemokine ligand 2; CCR2, C-C motif chemokine receptor 2; CXCR2, C-X-C motif chemokine receptor 2; ICAM1, intercellular adhesion molecule 1; IGF2R, insulin-like growth factor 2 receptor; and IL, interleukin.