Beta2-adrenergic receptor (B2AR) signaling is known to impairKeywords: Foxp3 · Noradrenaline · Sympathetic nervous system · Treg cell Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionLymphoid organs such as the spleen and the lymph nodes are richly innervated by the sympathetic nervous system (SNS), especially within T-cell areas [1]. Immune responses can be moduCorrespondence: Dr. Alexandre S. Basso e-mail: asbasso@unifesp.br lated by catecholamines released upon sympathetic activity only if immune cells are able to respond to them by expressing functional catecholaminergic receptors. Indeed, the beta2-adrenergic receptor (B2AR) has been described as the main adrenergic receptor expressed in immune cells, including dendritic cells, macrophages, CD4 + T cells, CD8 + T cells, and B cells [2,3]. Furthermore, increased noradrenaline release in the spleen followed by the activation of antigen-specific T and B cells has been already reported, indicating that an adaptive immune response can lead to enhanced SNS activity within lymphoid organs [4]. Taken 1002 Marcia. G. Guereschi et al. Eur. J. Immunol. 2013. 43: 1001-1012 sympathetic innervation of lymphoid organs, SNS activation due to adaptive immune responses, and the expression of adrenergic receptors by immune cells build a solid case supporting the concept that the SNS represents a feedback mechanism that is able to modulate immune responses [5]. Thus far, it has been shown that B2AR is expressed in CD4 + naïve T cells and Th1 clones while it is completely absent in Th2 clones [3,6]. CD4 + T-cell stimulation along with B2AR activation decreased IL-2 production and IL-2 receptor α-chain (CD25) expression in a cAMP-dependent way [3,[6][7][8]. Activation of Th1 clones in the presence of a B2AR agonist may also impair IL-2 and IFN-γ expression [6,7]. Furthermore, by selective inhibition of IL-12 production in LPS-stimulated human dendritic cells, B2AR agonists were found to block in vitro differentiation of neonatal CD4 + T cells into IFN-γ-producing cells, favoring IL-4 production instead [9]. Therefore information on SNS-mediated modulation of CD4 + T-cell immune responses via B2AR activation has been concentrated on the dichotomy Th1/Th2; and in general these data point to a role for B2AR activation in inhibiting the development of Th1 responses [6,8,9]. Very little is known on how adrenergic neurotransmitters could modulate the activity of other CD4 + T-cell subsets, among them Foxp3− T cells possess transcripts for the beta1-adrenergic receptor (B1AR) and the alpha2A-adrenergic receptor (A2aAR), besides the B2AR (Supporting Information Fig. 1A). Among those three, the B2AR is far more expressed than the other two (Supporting Information Fig. 1A). that Treg cells also express the B2AR, the B1AR, and the A2aAR (Supporting Information Fig. 1B). In Treg cells, B2AR was also expressed at higher levels as compared to B1AR and A2aAR (Supporting Information Fig. 1B). When comparing B2AR mRN...

Despite accumulating evidence indicating that neurotransmitters released by the sympathetic nervous system can modulate the activity of innate immune cells, we still know very little about how norepinephrine impacts signaling pathways in dendritic cells (DC) and the consequence of that in DC-driven T cell differentiation. In this article, we demonstrate that β2-adrenergic receptor (β2AR) activation in LPS-stimulated DC does not impair their ability to promote T cell proliferation; however, it diminishes IL-12p70 secretion, leading to a shift in the IL-12p70/IL-23 ratio. Although β2AR stimulation in DC induces protein kinase A–dependent cAMP-responsive element–binding protein phosphorylation, the effect of changing the profile of cytokines produced upon LPS challenge occurs in a protein kinase A–independent manner and, rather, is associated with inhibition of the NF-κB and AP-1 signaling pathways. Moreover, as a consequence of the inverted IL-12p70/IL-23 ratio following β2AR stimulation, LPS-stimulated DC promoted the generation of CD4+ T cells that, upon TCR engagement, produced lower amounts of IFN-γ and higher levels of IL-17. These findings provide new insights into molecular and cellular mechanisms by which β2AR stimulation in murine DC can influence the generation of adaptive immune responses and may explain some aspects of how sympathetic nervous system activity can modulate immune function.

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Highlights d Sympathetic nervous system (SNS) limits CNS autoimmune inflammation d Adrb2 signaling in immune cells mediates the SNS effects on EAE development d Adrb2-mediated SNS suppressive effects involve ICERdriven inhibition of CD4 + T cells

Acne vulgaris is a chronic disease of the pilosebaceous units presenting as inflammatory or noninflammatory lesions in individuals of all ages. The current standard of treatment includes topical formulations in the forms of washes, gels, lotions, and creams such as antibiotics, antibacterial agents, retinoids, and comedolytics. Additionally, systemic treatments are available for more severe or resistant forms of acne. Nevertheless, these treatments have shown to induce a wide array of adverse effects, including dryness, peeling, erythema, and even fetal defects and embolic events. Zinc is a promising alternative to other acne treatments owing to its low cost, efficacy, and lack of systemic side effects. In this literature review, we evaluate the effectiveness and side-effect profiles of various formulations of zinc used to treat acne.