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Sympathetic Nerves via β2-adrenoceptor Signaling Generate Circadian Rhythms and Govern Lymphocyte Recirculation in Lymph Nodes

Sympathetic Nerves Lymphocyte Recirculation
Sympathetic Nerves – Lymphocyte Recirculation

A new study, published in the Journal of Experimental Medicine (JEM), indicates that in mice, the sympathetic nervous system (SNS) innervation, through β2-adrenergic receptors activation controls the circadian dynamics and traffic of lymphocytes through the lymph nodes (LNs).

Cell trafficking among different anatomical sites is essential for proper functioning of the immune system. Recent studies have demonstrated that the frequency of neutrophil and monocyte migration from blood to tissues shows circadian oscillations that cause variations in the magnitude of inflammatory responses in tissue.

In addition to these innate immune cells, adaptive immune cells, represented by lymphocytes, have been suggested to possess diurnal fluctuations in their trafficking. However, the mechanisms and influences on immune responses remain unclear.

After surveying a LN for several hours, lymphocytes exit from the LN into lymph, return to blood flow, and travel to other lymphoid organs to continue antigen surveillance in the entire body (Cyster and Schwab, 2012).

The authors of the above-mentioned Journal of Experimental Medicine study have recently reported that inputs from adrenergic nerves control lymphocyte egress from, but not entry to, LNs through β2ARs.

Because adrenergic nerves release noradrenaline in a circadian manner and directly innervate lymphoid organs (Felten et al., 1985; Elenkov et al., 2000), they hypothesized that the β2AR-mediated control of lymphocyte recirculation through LNs might contribute to the diurnal variation of lymphocyte dynamics.

Both primary and secondary lymphoid organs are heavily innervated, mostly by the peripheral sympathetic nerves. Thus, locally released SNS neurotransmitters, such as norepinephrine (noradrenaline), neuropeptide Y (NPY) and ATP, in concert with circulating hormones such as epinephrine (adrenaline) regulate the full spectrum of innate and adaptive immune responses.

After 1904, when Loeper and Crouzon showed a pronounced leukocytosis, when adrenaline is injected subcutaneously in humans, many studies cleary indicated that the SNS controls immune cells distribution and traffic. More recently, evidence for circadian oscillations of components of the immune system has emerged. These circadian diurnal rhythms in tissues appear to be locally controlled by the SNS orchestrating the tissue-specific oscillations.

The systemic, circadian fluctuations of immune parameters include the number of circulating hematopoietic cells and naive T-cells, the pro- and anti-inflammatory cytokines such as interleukin-12 (IL-12) and IL-10, as well as leukocyte homing to the bone marrow and recruitment to skeletal muscle microvasculature.

Now, in the Journal of Experimental Medicine study, K Suzuki et al. from the WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan investigated whether signaling through β2-adrenergic receptors (β2ARs) is able to control lymphocyte recirculation through LNs, and thus driving the circadian fluctuations of the lymphocyte dynamics. This was based on the authors’ previous observations that inputs through lymphocyte β2ARs inhibit lymphocyte egress from LNs.

Thus, the authors evaluated the daily fluctuations of lymphocyte numbers and found that the accumulation of lymphocytes in peripheral LNs was associated with a rise in noradrenergic tone and activity, as evidenced by fluctuations in the noradrenaline’s concentrations in LNs.

Using 6-hydroxydopamine (6-OHDA) depletion and β2ARs-deficient mice, the researchers demonstrated that the input from the sympathetic/noradrenergic nerves to β2ARs on lymphocytes is essential and drives the circadian fluctuations of the lymphocyte dynamics.

Using an immunization protocol, the authors also observed that the induction of antibody and humoral immune response in LNs is boosted during periods of hingh noradrenergic tone and activity. This suggests that the noradrenergic input and the signaling through β2ARs may drive the nocturnal enhancement of adaptive immunity.

It appears that this study identifyies a novel mechanism contributing to the circadian rhythmicity in the immune system. The authors conclude that this mechanism, i.e., the β2ARs-mediated control by the SNS innervation generates circadian rhythms of lymphocyte egress from LNs, and controls the lymphocyte recirculation in these secondary lymphoid organs.

Importantly, this appears to be linked to a boost of humoral immune responses, during periods of high noradrenergic tone and activity.

Source: J Exp Med. 2016 Oct 31. pii: jem.20160723. [Epub ahead of print].
Read More: J Exp Med

Cover Image: The β2-adrenoceptor (blue) coupling to the heterotrimeric G protein GS (red, yellow, green) after binding of an agonist. Author: Brian Kobilka, Stanford University School of Medicine; https://en.wikipedia.org/wiki/History_of_catecholamine_research#/media/File:Receptor.kobilka.jpg Credit: Wikimedia Commons.