Dual cholinergic signals regulate daily migration of hematopoietic stem cells and leukocytes

Abstract

Hematopoietic stem and progenitor cells (HSPCs) and leukocytes circulate between the bone marrow (BM) and peripheral blood following circadian oscillations. Autonomic sympathetic noradrenergic signals have been shown to regulate HSPC and leukocyte trafficking, but the role of the cholinergic branch has remained unexplored. We have investigated the role of the cholinergic nervous system in the regulation of day/night traffic of HSPCs and leukocytes in mice. We show here that the autonomic cholinergic nervous system (including parasympathetic and sympathetic) dually regulates daily migration of HSPCs and leukocytes. At night, central parasympathetic cholinergic signals dampen sympathetic noradrenergic tone and decrease BM egress of HSPCs and leukocytes. However, during the daytime, derepressed sympathetic noradrenergic activity causes predominant BM egress of HSPCs and leukocytes via β3–adrenergic receptor. This egress is locally supported by light-triggered sympathetic cholinergic activity, which inhibits BM vascular cell adhesion and homing. In summary, central (parasympathetic) and local (sympathetic) cholinergic signals regulate day/night oscillations of circulating HSPCs and leukocytes. This study shows how both branches of the autonomic nervous system cooperate to orchestrate daily traffic of HSPCs and leukocytes.

Circadian Features of Neutrophil Biology

“…Sympathetic nerves that innervate the BM deliver diurnal adrenergic signals to stromal cells through β3-adrenergic receptors, which inhibit CXCL12 expression and generate oscillatory expression of the chemokine (42). Cholinergic signals from the parasympathetic nervous system (PNS), in turn, have been shown to inhibit adrenergic activity of the murine SNS at night (43), altogether establishing tight temporal patterns in the BM. In mice, downregulation of CXCL12 at daytime drives the circadian egress of HSCs (42), and the release of neutrophils at this same time also coincides with decreased CXCL12 (40) (Figure 1).…”

Time-of-Day-Dependent Trafficking and Function of Leukocyte Subsets

“…However, whether the SNS is generally involved in the underlying rhythmic entrainment of peripheral tissues [23,24] is debated given that peripheral circadian clock rhythmicity is retained in mice deficient in dopamine b-hydroxylase (Dbh À/À ), and thus in the absence of adrenergic signaling [25]. In addition, the GDNF family receptor a2 (GFRa2) functions in the development/survival of cholinergic neurons, and recent observations in GFRa2-deficient mice (Gfra2 À/À ) have further implicated the parasympathetic nervous system (PNS) in the rhythmic regulation of leukocyte migration, counterbalancing the SNS [26]. On the one hand, light onset in the morning acutely activates sympathetic b 3 -adrenoreceptors to induce the mobilization of hematopoietic cells from the BM in mice [7], but, on the other hand, light can also induce sympathetic cholinergic nerves to reduce homing, thereby facilitating the release of cells into blood [26].…”

“…In addition, the GDNF family receptor a2 (GFRa2) functions in the development/survival of cholinergic neurons, and recent observations in GFRa2-deficient mice (Gfra2 À/À ) have further implicated the parasympathetic nervous system (PNS) in the rhythmic regulation of leukocyte migration, counterbalancing the SNS [26]. On the one hand, light onset in the morning acutely activates sympathetic b 3 -adrenoreceptors to induce the mobilization of hematopoietic cells from the BM in mice [7], but, on the other hand, light can also induce sympathetic cholinergic nerves to reduce homing, thereby facilitating the release of cells into blood [26]. By contrast, at night, central parasympathetic cholinergic signals can dampen sympathetic noradrenergic tone and decrease BM egress of HSPCs and leukocytes.…”

“…By contrast, at night, central parasympathetic cholinergic signals can dampen sympathetic noradrenergic tone and decrease BM egress of HSPCs and leukocytes. Owing to increased plasma adrenaline concentrations and HPA axis activity, the higher activation of b 2 -adrenoreceptors at this time can mediate the homing of cells to tissues in mice [26]. Thus, sympathetic and parasympathetic nerves can serve opposite but cooperative roles to orchestrate rhythmic leukocyte release and homing.…”

Daily light and darkness onset and circadian rhythms metabolically synchronize hematopoietic stem cell differentiation and maintenance: The role of bone marrow norepinephrine, tumor necrosis factor, and melatonin cycles

“…The cholinergic nervous system as well plays a role in orchestrating the daily HSPCs and leukocyte traffic. At night, the central parasympathetic cholinergic signals inhibit the noradrenergic tone to reduce BM HSPCs and leukocyte egress, while during daylight, via b3 receptor-NE signaling enhanced BM HSPC and leukocyte egress together with light-induced sympathetic cholinergic activity, which also reduces BM vascular cell adhesion and homing [98]. The parasympathetic cholinergic pathway have anti-inflammatory effects [60,99] that limit the continued secretion of cytokines such as TNF and NF-kB activation [60].…”