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.
Read More: jimmunol.org
AI–Assisted Updates (see footnote below)
A 2018 study, investigated norepinephrine (NE) role in a mouse model of collagen-induced arthritis (CIA), a model for rheumatoid arthritis. It found that NE inhibits Th17 cell differentiation and function via β2-AR signaling. Specifically, NE treatment decreased the expression of RORγt, a key transcription factor for Th17 cells, and reduced IL-17A production, suggesting an anti-inflammatory effect. This finding contrasts with earlier suggestions that NE favors Th17 differentiation, indicating context-dependent effects, possibly due to direct action on T cells rather than DCs. This suggests NE may mitigate Th17-driven inflammation in autoimmune conditions, with potential therapeutic implications for rheumatoid arthritis.
A 2020 review explores how the sympathetic nervous system, via catecholamines like NE and epinephrine, regulates immune functions through adrenergic receptors. It highlights that β2-AR signaling in DCs can suppress IL-12 production, which may indirectly affect the IL-12/IL-23 ratio. While not directly addressing IL-23, the suppression of IL-12 could tilt the balance toward IL-23, potentially favoring Th17 responses. This review also notes circadian rhythms in NE levels influencing immune function, adding a temporal dimension to its effects. This finding supports the idea that NE modulates DC cytokine profiles, with potential downstream effects on T cell polarization, though further studies are needed to quantify IL-23 changes.
A 2021 review discusses adrenergic receptor signaling in neuroimmune interactions, focusing on DCs. It notes that β2-AR stimulation in lipopolysaccharide (LPS)-challenged DCs leads to increased IL-23 secretion compared to IL-12p70, referencing a 2016 study (not included here due to date). This shift can influence T cell differentiation toward a Th17 phenotype, with implications for inflammatory responses. The review also mentions NE reducing IL-12 and enhancing IL-10 in DCs, further supporting its role in modulating cytokine balances. This reinforces the notion that NE can favor IL-23 production in DCs, potentially promoting Th17 differentiation, but highlights the need for primary studies post-2016 to confirm these effects.
Synthesis and Controversies
The findings reveal a complex picture: NE appears to have dual effects, depending on the cell type and context. In DCs, it seems likely to suppress IL-12 and potentially increase IL-23, favoring Th17 differentiation, as suggested by the 2021 review. However, in T cells, particularly Th17 cells, NE can inhibit their function, as shown in the 2018 study on rheumatoid arthritis. This duality suggests that the net effect in vivo may depend on the balance between direct effects on T cells and indirect effects via DCs. The controversy lies in reconciling these findings, with some studies suggesting pro-inflammatory effects through IL-23 and others anti-inflammatory effects through Th17 inhibition.
Unexpected Detail
An unexpected detail is the temporal aspect, with the 2020 review noting that NE’s effects may follow circadian rhythms, potentially influencing immune responses differently at various times of day. This adds a layer of complexity to therapeutic strategies targeting NE in immune modulation.
Conclusion
The recent literature from 2017 onwards suggests that norepinephrine modulates immune responses through effects on dendritic cells and T cells, with potential impacts on IL-12, IL-23, and Th17 differentiation. The evidence leans toward a context-dependent role, with pro-inflammatory effects via IL-23 in DCs and anti-inflammatory effects via Th17 inhibition in certain disease models. Further research is needed to clarify these interactions, particularly in human models and under varying stress conditions.
Professional AI assistance:
Updates assisted and generated by an Artificial Intelligence (AI) using the professional services of Zlatin Balevsky (contact@balevsky.ai).
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