In a study published in the journal Cytokine, Michela Manni, Richard Granstein and Georges Maestroni, from the Center for Experimental Pathology, Locarno, Switzerland, provide new evidence suggesting that catecholamines, through activation of beta2-adrenoreceptors (ARs) on immune cells, may drive, in certain conditions, Th17 immune responses.
Dendritic cells (DCs) are professional antigen presenting cells (APCs) involved in the initiation and polarization of the adaptive immune response. The priming of Th cell subsets is orchestrated by cytokines produced by DCs that sense pathogen-associated molecular patterns (PAMPs) and local microenvironmental factors. Th17 cells are a recently discovered lineage of effector CD4+ T cells characterized by the production of IL-17, IL-21 and IL-22.
Th17 cells provide defense against extracellular bacteria but are also implicated in autoimmune disorders. In mice, the development of a Th17 immune response depends on the presence of the proinflammatory cytokines IL-6 and TGF-β1 and is suppressed by the Th1-type cytokines IFN-γ and IL-12 and by the Th2-type cytokine IL-4. Furthermore, IL-23 was shown to be important for Th17 expansion.
Previous research demonstrates that adrenergic receptors modulate cytokine production in DCs and affect their Th cell priming ability. Thus, activation of β2-adrenergic receptors (β2-ARs) in DCs stimulated by Toll-like receptor (TLR) agonists hampers IL-12 and stimulates IL-10 production resulting in reduced migration and Th1 priming.
In the Cytokine article, Michela Manni, Richard Granstein and Georges Maestroni, from the Center for Experimental Pathology, Locarno, Switzerland, investigated whether β-AR activation could influence NOD2 signaling along with its cross-talk with TLR-2 and the resulting Th cell priming ability by murine DCs.
The authors found that the beta2-AR agonist salbutamol is able to modulate cytokine production in dendritic cells (DCs) stimulated with MDP or simultaneously by both TLR-2 and NOD2 ligands, resulting in a cytokine pattern that directs Th17 priming.
In summary, the study shows that β2-AR activation may modulate Th cell priming in favor of an IL-17 immune response. The investigators found that the β2-AR agonist salbutamol enhanced IL-6 protein and gene expression in murine DCs stimulated with the NOD2 agonist MDP. IL-12 mRNA and protein were inhibited by salbutamol in PAM and PAM+MDP treated cells. This result confirms the ability of β2-AR agonists to inhibit IL-12 production in DCs stimulated by various PAMPs as previously reported by the authors and others.
The authors report that IL-12/IL-23 p40 subunit expression is downregulated by salbutamol while IL-23 p19 is upregulated, explaining the resulting absence of influence of salbutamol at the protein level. These results suggest that in the presence of PAMPs stimulating NOD2 or both TLR-2 and NOD2, activation of β2-ARs in DCs results in a cytokine pattern characterized respectively by induction of IL-6 or inhibition of IL-12 without affecting IL-23. These cytokine patterns are favorable for Th17 priming.
These findings have both basic and clinical relevance. Indeed, besides being important effectors against extracellular bacteria and fungi, IL-17 and Th17 cells have also been implicated in the pathogenesis of autoimmune and inflammatory disorders.
Contrary to the concept that beta2-AR agonists are immunosuppressive agents, this report indicates that in combination with TLR-2 and/or NOD2 activation, stimulation of beta2-ARs on dendritic cells may enhance an IL-17-type immune response.
Catecholamines and β2-ARs might be involved in the defense against extracellular bacteria and in the pathogenesis of inflammatory diseases by modulating Th17 polarization.
Thus, administration of β2-AR agonists might conceivably be useful in augmenting IL-17 type immunity for therapeutic purposes in some situations, such as in the setting of an infection where a microorganism product is stimulating TLR and/or NOD2 activation. It should be noted that NOD2 is the intracellular pattern recognition receptor (PRR) that senses MDP derived from both gram-positive and gram-negative bacteria.
These findings may have implications for conditions such as asthma/allergy, autoimmunity or psoriasis, where sympathetic-immune dysfunction or stress-induced exacerbations have been described. For example, as IL-17 is increased in skin inflammatory disorders such as psoriasis, this study suggest that stress-induced release of catecholamines by the sympathetic nervous system with consequent stimulation of Th17-type immunity may contribute to stress induced exacerbation of psoriasis.