Norepinephrine May Shift the IL-12/IL-23 Ratio of Dendritic Cells towards IL-23 Predominance thus Favoring Th17 Differentiation

Norepinephrine shift IL 12IL-23 Ratio il-23
Norepinephrine – IL-12/IL-23 Ratio – IL-23 Predominance

A new study published in the January 15, 2016 issue of the Journal of Immunology indicates that in murine bone marrow–derived dendritic cells (DCs), norepinephrine, via stimulation of β2-adrenoceptors, is able to promote a shift in the IL-12/IL-23 ratio.

Primary and secondary lymphoid organs receive a rich autonomic nervous system innervation, mainly by the peripheral sympathetic nervous system (SNS).

Lymphoid organs are not only extensively hardwired but also the immune cells’ activity is tuned by norepinephrine (noradrenaline), neuropeptide Y and ATP released locally from the sympathetic nerve terminals.

Thus, major SNS mediators and neurotransmitters may regulate key immune functions such as antigen presentation, secretion of cytokines and antibodies, selection of T helper (Th)1 or Th2 responses, regulatory T cells function, lymphocytes traffic and proliferation and differentiation (IJ Elenkov et al., Pharmacol Rev, 2000, 52:595-638).

Particularly in the spleen and lymph nodes, the sympathetic innervation is restricted to the T cell zones where dendritic cells (DC) are also present (3, 4). It was reported that immune cells, including T lymphocytes and DC, express a– and beta-adrenergic receptors which allows them to respond to NE.

Dendritic cells are potent APC and play an important role in linking innate and adaptive immune responses.  Usually, DC stimulated with LPS produce higher levels of IL-12p70 than IL-23, which is associated with Th1 differentiation. In contrast, higher levels of IL-23 than IL-12p70 are produced by zymosan-activated DC, which can instead facilitate the orchestration of Th17-mediated immune response.

In terms pf cytokine secretion, it was shown that stimulation of beta2 -adrenergic receptor modulates cytokine production by activated DC, primarily by inhibiting some proinflammatory cytokines, such as TNF-alpha, IL-12, and IL-6, and by increasing IL-10 and IL-33 release by these cells.

In the Journal of Immunology study, Maisa Takenaka and colleagues from the Federal University of São Paulo, Brazil, and the Brigham and Women’s Hospital, Harvard Medical School, US, show that immature DCs express both α- and β-adrenergic receptors, and particularly, the β2-subtype of adrenoreceptors.

Stimulation of DCs β2-adrenoceptors by norepinephrine or fenoterol (selective β2-adrenoceptor agonist) induced an inhibition of IL-12p70 secretion, without affecting the IL-23 production. This resulted in a shift in the IL-12p70/IL-23 ratio in favor of IL-23.

Consistent with previous findings the authors observed that the β2AR-mediated shift in the IL-12p70/IL-23 ratio following LPS challenge of DC was due to decreased IL-12p70 production (with no alteration in IL-23 secretion) and was accompanied by increased IL-10 production.

DCs function and cytokine profiles are known to drive the generation of adaptive-immune responses. In the co-cultures of naive T cells with DCs treated with β2-adrenoceptor agonist, the researchers detected a decrease in IFN-γ, but an increase in IL-17A production. IFN-γ and IL-17A are, respectively, Th1– and Th17 cell–derived cytokines.

This suggests that in lymphoid organs, the major SNS neurotransmitter norepinephrine may facilitate Th17 responses but suppress Th1 cell differentiation.

These observations substantiate previous work indicating that catecholamines ‘dictate’ dendritic cells to generate a dominant Th2/Th17 phenotype, and that the β2-adrenoceptor signaling alters DC cytokine expression to favor Th17 cell development (BJ Kim & Jones HP, Brain Behav Immun, 2010, 24:1126-36; M Manni, Granstein RD & Maestroni G, Cytokine, 2011; 55:380-6).

Takenaka et al. suggest that their results may help explain how the sympathetic nervous system regulates the immune function, and importantly, how the activity of this system may affect the onset or progression of some inflammatory/autoimmune diseases.

Th17 immune responses play a key role in chronic inflammation and numerous autoimmune diseases. It remains to be seen how and to what extent the basal or stress-induced SNS activity, and its effect on Th17 cells, may alter the course of these conditions and diseases.

Source: J Immunol, 2016; 196:637. doi: 10.4049/jimmunol.1501206. Epub 2015 Dec 11.
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