Circadian oscillations – leukocyte migration
In the August 2012 issue of Immunity, Scheiermann et al. describe a series of experiments that elegantly illustrate the patterns of leukocyte homing to the bone marrow and recruitment to skeletal muscle, and how they are affected by photic and adrenergic input.
Scheiermann et al. begin by establishing that circadian oscillations are present in peripheral white blood cell counts, which peak 5 hours after onset of light (zeitgeiber time, ZT5) with a trough at ZT13, while bone marrow homing exhibits an antiphase pattern, wherein the number of homed hematopoietic cells peak at ZT13 with a trough at ZT1.
They also noted significantly increased numbers of rolling and adherent leukocytes within bone marrow sinusoids at ZT13 as compared to ZT5. They then stained skeletal muscle (cremaster) and noted increased numbers of both CD45+ and F4/80+ extravasated cells at ZT13 compared to ZT5. To trigger an inflammatory response, the authors exteriorized muscle tissue, thus simulating trauma conditions, and noted significantly increased numbers of adherent neutrophils and monocytes at night.
In a more in-depth look at the mechanisms for these fluctuations, the authors used wild-type, Icam -/-, Ccr2 -/-, and Sele/Selp -/- mice and compared extravasated and adherent leukocyte numbers in skeletal muscle and bone marrow sinusoids. They found correlations between expression of promigratory factors within endothelial cells and circadian oscillations in leukocyte counts – ICAM-1 and CCL-2 with adherent leukocytes in muscle and endothelial selectins and VCAM-1 with both adhesion and rolling of leukocytes in bone marrow.
To demonstrate involvement of adrenergic nerves in leukocyte count oscillations in skeletal muscle and bone marrow respectively, the authors denervated the genitofemoral nerve and ablated the superior cervical ganglion unilaterally. In both tissues, circadian oscillations were abolished in the denervated side. Furthermore, they showed that circadian oscillations in leukocyte recruitment to the bone marrow were significantly reduced in both β2- and β3-adrenoreceptor deficient mice.
The role of photic cues was demonstrated by inducing experimental jet lag, which abolished the circadian oscillations in leukocyte recruitment to skeletal muscle and homing to bone marrow, as well as ICAM-1 expression. In the setting of inflammation (TNF-α injection), ICAM-1 expression increased and circadian rhythms of leukocyte recruitment were preserved, but if the animal was jet-lagged, endothelial cell adhesion was reduced and circadian rhythms in leukocyte count and neutrophil infiltration were abolished.
The authors then illustrated the potential clinical significance of the above findings through models of bone marrow transplant, septic shock, and sickle cell vaso-occlusion. The authors found that most animals undergoing bone marrow transplant in the morning died within 1 month, while all animals transplanted at ZT13 survived. Also, treating mice with isoproterenol, a pan-β-receptor agonist, led to increased selectin and VCAM-1 expression, increased leukocyte recruitment, and increased survival with fewer transplanted cells.
When vaso-occlusive crisis was induced at night in mice with sickle cell disease, white blood cell and red blood cell interactions increased and venular blood flow rates decreased, with a corresponding decrease in survival as compared to mice challenged during the daytime.
In a model of septic shock, mice injected with a lethal dose of endotoxin at night versus during the day had decreased survival. Icam -/- mice showed no significant disparity in survival between nighttime and daytime challenges, suggesting that ICAM-1 is heavily involved in this process.
According to the authors, the rhythmic pattern of leukocyte recruitment may have evolved for the benefit of having readily available tissue phagocytes for enhancement of the response to pathogens during periods of injuries and/or encounters with microorganisms. Furthermore, they hypothesize that their results are relevant to cardiovascular diseases, and that the circadian leukocyte adhesion or an exaggeration thereof might contribute to triggering acute vascular diseases in the morning.
Taken together, this group of experiments demonstrates from various angles the critical role and clinical relevance of circadian oscillations in leukocyte migration. The input from noradrenergic nerves and the clinical relevance for various inflammatory diseases is fascinating and merits further studies.
Source: Immunity. 2012 Aug 24;37(2):290-301.
Updates
A 2020 review published in Frontiers in Immunology discusses how different neural signals regulate circadian hematopoietic stem cells (HSCs) egress, homing, maintenance, proliferation, and differentiation. And, in particular, the critical role of different neurotransmitter receptors in the bone marrow microenvironment that channel these neural signals and regulate antagonistic processes according to circadian cues and organismal demands.
In the mouse system, sympathetic postganglionic terminals convey the circadian information from the suprachiasmatic nucleus to the bone marrow (BM), where noradrenaline is locally released. The adrenergic signals activate β3-adrenergic receptors in BM nestin+ mesenchymal stem cells (MSCs) and modulate the C-X-C motif chemokine 12 (CXCL12) production.
This regulation leads to daily fluctuations in BM CXCL12 levels that inversely correlate with HSC numbers in the bloodstream. At daytime (the resting period in mice), light-induced noradrenergic signals downregulate CXCL12 expression via Sp1 transcription factor and promote HSC egress to the bloodstream. At night, BM CXCL12 levels are restored and HSCs preferentially return to the BM (also referred to as “HSC homing”).
Besides the described role for β3-adrenergic receptor, β2-adrenergic receptor appears to regulate clock gene expression in BM stromal cells and cooperates with β3-adrenergic receptor in HSPC mobilization induced by granulocyte colony-stimulating factor (G-CSF).
Selective predominance of different β-adrenergic signaling at daytime and night, together with differential affinities of catecholamines for β-adrenergic receptors, may explain how sympathetic noradrenergic signals trigger BM egress or homing at different time points.
The authors of this review propose that a robust circadian rhythmicity in β-adrenergic receptor expression in BM stromal cells allows for these fine-tuned oscillations. Whereas, β3-adrenergic receptor expression is higher after light exposure (when BM egress becomes overriding), β2-adrenergic receptor expression predominates at night (when BM homing is maximum).
An additional role for sympathetic cholinergic innervation in this circadian regulation appears to be the inhibition of β3-adrenergic receptor expression at night.
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