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See related article on pg 123 Deregulation of Adenosine Receptors in Psoriatic Epidermis: An Option for Therapeutic Treatment Stefania Merighi 1 , Pier Andrea Borea 1 , Katia Varani 1 and Stefania Gessi 1 Purinergic signaling is involved in psoriasis, a chronic skin disease characterized by increased epidermis cell growth. In particular, Andrés et al. focus on the keratinocyte biology modulated by adenosine receptors providing evidence that the A 2B subtype plays a prominent role in the reduction of keratinocyte prolif- eration whereas A 2A and A 2B agonists have antiinflammatory effects independent of adenosine receptors. The authors report that psoriatic epidermis presents a deregulated adenosine receptor expression profile with reduced A 2B and increased A 2A . Journal of Investigative Dermatology (2017) 137, 11e13. doi:10.1016/j.jid.2016.08.001 Psoriasis and adenosine Psoriasis is a common relapsing and remitting autoimmune disease, affecting the skin and joints, now thought to be caused by the dysregula- tion of cytokines controlling inflamma- tory pathways, a mechanism that likely contributes to the various comorbidities observed in patients affected by it. Biologic treatments specifically target the altered inflammatory milieu, and they have been shown to be effective for moderate to severe psoriasis, commonly after other systemic treatments have failed. However, the first-line inexpen- sive systemic treatment of psoriasis is represented by methotrexate, an inhibi- tor of dihydrofolate reductase that blocks DNA synthesis and cell mitosis of rapidly dividing cells. Importantly, it has a well-established safety profile. It is well known that many of its effects are mediated by the activation of an aden- osine receptor. In fact, methotrexate in- duces adenosine release both “in vitro” and “in vivo,” in both animal models of inflammation and patients with rheu- matoid arthritis (Cronstein, 2010). Adenosine concentrations in normal physiological conditions are low, in the nanomolar range, due to the activity of enzymes and transporters, but they in- crease in different pathologic settings, up to micromolar levels. Interestingly, high levels of adenosine have been re- ported to be found in the blood of pa- tients with psoriasis (Burnstock et al., 2012). Indeed, adenosine is a ubiqui- tous autacoid, one that exerts a wide variety of physiological effects through interaction with four G protein-coupled receptors, named A 1 ,A 2A ,A 2B , and A 3 . They are able to modulate adenylyl cyclase activity, being A 1 and A 3 in- hibitors, whereas A 2A and A 2B are stim- ulators of this enzyme through interactions with G i and G s proteins, respectively. In addition, A 2B and A 3 are also coupled to phospholipase C, via G q proteins, thereby increasing calcium levels (Borea et al., 2015). Finally, all of these molecules modulate mitogen- activated protein kinases, with impor- tant consequences in the modulation of cell proliferation (Borea et al., 2016). Andre´s et al. (2017) investigated the role of adenosine receptors in ker- atinocyte proliferation, and they re- ported that the A 2B receptor inhibits proliferation whereas the A 2A subtype stimulates it. In addition, the authors focused on the antiinflammatory effects mediated by A 2A and A 2B agonists and concluded that these are not related to adenosine receptor binding. Effects of adenosine receptors on keratinocyte proliferation The literature includes few studies concerned with the therapeutic appli- cation of adenosinergic signaling in the skin, and the effects of adenosine regulation of epidermal cells are not well studied (Merighi et al., 2002). Adenosine receptor expression has been shown in keratinocytes, and the A 2B receptor is the major receptor subtype (Andre´s et al., 2017; Braun 1 Department of Medical Sciences, University of Ferrara, Via Fossato di Mortara, Ferrara, Italy Correspondence: Pier Andrea Borea, Department of Medical Sciences, Pharmacology Section, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy. E-mail: bpa@unife.it or Katia Varani, Department of Medical Sciences, Pharmacology Section, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy. E-mail: vrk@unife.it ª 2016 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. COMMENTARY www.jidonline.org 11