Role of HCA2 (GPR109A) in nicotinic acid and fumaric acid ester-induced effects on the skin

Pharmacology & Therapeutics 136 (2012) 1–7

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Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera

Role of HCA2 (GPR109A) in nicotinic acid and fumaric acid ester-induced effects on the skin Julien Hanson a, b,⁎, Andreas Gille c, 1, Stefan Offermanns d, e a

Molecular Pharmacology, GIGA-Signal Transduction Unit, University of Liège, CHU, B34 (+4), 4000 Liège, Belgium Medicinal Chemistry, Drug Research Center-CIRM, University of Liège, Belgium Institute for Experimental and Clinical Pharmacology and Toxicology, University of Heidelberg, Medical Faculty Mannheim, Maybachstrasse 14, 68169 Mannheim, Germany d Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany e Medical Faculty, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany b c

a r t i c l e

i n f o

Keywords: Nicotinic acid Monomethyl fumarate Flushing Psoriasis HCA2 Keratinocytes Cyclooxygenase

a b s t r a c t Nicotinic acid (NA) and fumaric acid esters (FAE) such as monomethyl fumarate or dimethyl fumarate are drugs that elicit a cutaneous reaction called flushing as a side effect. NA is used to reduce progression of atherosclerosis through its anti-dyslipidemic activity and lipid-independent mechanisms involving immune cells, whereas FAE are used to treat psoriasis via largely unknown mechanisms. Both, NA and FAE, induce flushing by the activation of the G-protein-coupled receptor (GPCR) Hydroxy-carboxylic acid receptor 2 (HCA2, GPR109A) in cells of the epidermis. While the wanted effects of NA are at least in part also mediated by HCA2, it is currently not clear whether this receptor is also involved in the anti-psoriatic effects of FAE. The HCA2‐mediated flushing response to these drugs involves the formation of prostaglandins D2 and E2 by Langerhans cells and keratinocytes via COX-1 in Langerhans cells and COX-2 in keratinocytes. This review summarizes recent progress in the understanding of the mechanisms underlying HCA2-mediated flushing, describes strategies to mitigate it and discusses the potential link between flushing, HCA2 and the anti-psoriatic effects of FAE. © 2012 Elsevier Inc. All rights reserved.

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 2. HCA2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. HCA2-mediated cutaneous effects . . . . . . . . . . . . . . 4. HCA2 and psoriasis . . . . . . . . . . . . . . . . . . . . . 5. Physiological role of HCA2 in Langerhans cells and keratinocytes 6. Strategies to mitigate nicotinic acid-induced cutaneous effects . 7. Conclusions and future directions . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Abbreviations: NA, nicotinic acid; FAE, fumaric acid ester; GPCR, G-protein-coupled receptor; HCA2, hydroxy-carboxylic acid receptor 2; PG, prostaglandin; COX, cyclooxygenase; MMF, monomethyl fumarate; DMF, dimethyl fumarate; cPLA2, cytosolic phospholipase A2; GRK, GPCR kinase; FFA, free fatty acid. ⁎ Corresponding author at: Molecular Pharmacology, GIGA-Signal Transduction, University of Liege, CHU, B34, Tour GIGA (+4), 1, av. de l'Hopital, B-4000 Liege, Belgium. Tel.: +32 43664748; fax: +32 43664362. E-mail address: [email protected] (J. Hanson). 1 Present address: CSL Limited, 45 Poplar Road, 3052 Parkville, Australia. 0163-7258/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pharmthera.2012.06.003

Nicotinic acid (NA) (Fig. 1) belongs to the B vitamin class (B3) and has originally been used to treat pellagra, a disease caused by chronic deficiency of vitamin B3. Rudolf Altschul et al. were the first to describe the effect of NA on human lipid metabolism (Altschul et al., 1955), and for almost 50 years NA has been used to treat dyslipidemia and to reduce cardiovascular risk. NA has beneficial effects on plasma levels of all major lipids decreasing total cholesterol, LDL-cholesterol, triglycerides and

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O

O OH

O

HO O

N Nicotinic acid

Monomethyl fumarate

Fig. 1. Structures of nicotinic acid and monomethyl fumarate.

et al., 1980) and activates various downstream effectors depending on the cell type. In immune cells, activation of HCA2 leads via the Gβγ-complex to an activation of phospholipase C-β and an increase of intracellular Ca 2+ (Exton, 1996; Rhee, 2001; Gille et al., 2008). In adipocytes, activation of the receptor results in Gαi-mediated inhibition of adenylyl cyclase and subsequently of protein kinase A, resulting in reduced lipolysis and decreased release of free fatty acids into the circulation (Tunaru et al., 2003; Zhang et al., 2005). HCA2 is expressed in white and brown adipose tissue, keratinocytes and various immune cells including monocytes, macrophages, neutrophils and dendritic cells including Langerhans cells (Soga et al., 2003; Wise et al., 2003; Maciejewski-Lenoir et al., 2006; Gille et al., 2008; Hanson et al., 2010). The most homologous protein to HCA2 is HCA3, which is found in humans but not in rodents and shares 96% homology with HCA1. Reports suggest that this receptor is expressed in a pattern similar to HCA1 in adipose tissue, neutrophils, monocytes and macrophages thus potentially providing an alternative therapeutic target (Bermudez et al., 2011; Offermanns et al., 2011).

lipoprotein(a), while increasing HDL-cholesterol levels (Knopp et al., 1998; Goldberg et al., 2000; Carlson, 2006). Notably, NA is currently the most efficacious drug available to increase HDL-cholesterol levels (Brown & Zhao, 2008; Digby et al., 2009), and it was the first drug shown to reduce mortality in patients with coronary artery disease (Canner et al., 1986). The mechanism by which NA affects dyslipidemia and progression of atherosclerosis has been reviewed elsewhere (Gille et al., 2008; Kamanna & Kashyap, 2008; Lukasova et al., 2011a). Monomethyl fumarate (MMF) (Fig. 1) has been used in combination with other fumaric acid esters (FAE) in the treatment of psoriasis and has been shown to reduce the keratinocytes proliferation and the infiltration of the dermis and epidermis by inflammatory cells in patients affected with psoriasis (Mrowietz & Asadullah, 2005). The German chemist Schweckendiek, who suffered from psoriasis himself, postulated that the cause of the disease was a defect in the citric acid cycle, of which fumaric acid is an intermediate, and he reported that FAE taken orally had an anti-psoriasis effect (Schweckendiek, 1959). Following subsequent studies supporting the anti-psoriatic activity of these preparations (Schäfer, 1984), FAE have been available since 1994 in German-speaking countries as a commercial preparation of which dimethyl fumarate (DMF) is the principal active component (Fumaderm®). Following oral application, DMF is rapidly converted by first-pass metabolism to the monoester, which is thought to be the active form (Rostami Yazdi & Mrowietz, 2008). Clinical trials have demonstrated that FAE reduce the psoriatic lesion area and the severity index after 12–16 weeks of treatment, and are considered to be safe as a long term treatment (Mrowietz et al., 1998; Gollnick et al., 2002; Hoefnagel et al., 2003; Reich et al., 2009; Wain et al., 2009). It has recently been shown that skin flushing induced by MMF and NA occurs in both cases due to the activation of the G-protein-coupled receptor HCA2 and involves identical cellular mechanisms (Hanson et al., 2010). In this review, we summarize the mechanism of skin flushing and discuss the implication of the epidermal effects of the HCA2 agonists NA and MMF with regard to their clinical use.

Flushing in response to NA was first described by investigators who were treating patients with NA for pellagra (Smith et al., 1937; Spies et al., 1938). It is characterized by redness and warmth due to vasodilation of dermal blood vessels, and by various sensory phenomena such as tingling and burning. The flushing phenomenon lasts typically for an hour and usually starts in the head region thereafter expanding to the arms and trunk, and sometimes to legs and feet. In both humans and mice, the increase in dermal blood perfusion in response to nicotinic acid occurs in a biphasic fashion; a relatively short first phase is followed by a longer lasting second phase (Goldsmith & Cordill, 1943; Benyó et al., 2005). Although benign, the discomfort associated with flushing causes between 5% and 20% of patients taking NA to discontinue the treatment (Gray et al., 1994; Jacobson, 2010). Because the use of NA is greatly compromised by its major side effect, it is of clinical relevance to improve our understanding of the mechanism responsible for NA-induced flushing. Although MMF has only recently been identified as an HCA2 agonist (Tang et al., 2008), flushing is known as a side effect of FAE since early clinical studies and has led to the discontinuation of treatment in some patients (van Dijk, 1985; Nieboer et al., 1989; Nieboer et al., 1990). In a mouse model of flushing, MMF has been shown to elicit an HCA2-mediated flushing response, with a mechanism identical to NA-mediated flushing (Hanson et al., 2010).

2. HCA2

3.2. The epidermis as a site of flush initiation

The receptor activated by NA and MMF, formerly named GPR109A or HM74a in humans and PUMA-G in mice, has recently been renamed by an IUPHAR nomenclature committee as hydroxy-carboxylic acid (HCA) receptor-2 (HCA2) (Offermanns et al., 2011). HCA2 belongs to the group of G-protein-coupled receptors and was listed as an orphan receptor after its cloning in 1993 (Nomura et al., 1993). In 2003, HCA2 was shown to be a receptor for NA (Soga et al., 2003; Tunaru et al., 2003; Wise et al., 2003) and to mediate the antilipolytic effects of NA. Using mice lacking HCA2, Benyó et al. subsequently showed that binding of NA to the receptor was also responsible for the cutaneous vasodilation observed during flushing (Benyó et al., 2005). Additionally, in 2008, Tang et al. showed in vitro that MMF was a potent full agonist of HCA2 receptors whereas DMF was inactive (Tang et al., 2008). Whether the HCA2 receptor is involved in the anti-psoriatic effects of FAE and whether NA has anti-psoriatic effects are still open questions (vide infra). HCA2 is coupled to the Gi family of G-proteins (Aktories

The fact that local application of NA esters like methyl nicotinate or benzyl nicotinate to the skin surface produced a localized flushing response (Tur et al., 1983) indicates that the mechanism underlying the flushing response is confined to the skin. This hypothesis was supported by the finding that HCA2 is expressed in the epidermis, in particular in keratinocytes (Tang et al., 2008; Dunbar & Gelfand, 2010; Hanson et al., 2010; Bermudez et al., 2011) and Langerhans cells (Benyó et al., 2006; Maciejewski-Lenoir et al., 2006). The epidermis is avascular and consists mainly of keratinocytes arranged in a stratified squamous epithelium. It is the interface between the environment and the organism, and is a first-line defense system in contact with potential pathogens. Langerhans cells are specialized epidermal dendritic cells that make up to 2–4% the total epidermal cell population. They establish dense networks within the basal and supra-basal layers of the epidermis and serve their function by uptake and presentation of antigens. Following antigen contact, Langerhans cells become activated and migrate from

3. HCA2-mediated cutaneous effects 3.1. Flushing

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the epidermal compartment to the draining lymph node where they present processed fragments of antigen to effector cells of the adaptive immune system (Valladeau & Saeland, 2005). Mouse models were of pivotal importance in the elucidation of the mechanism of flushing. Mice that were depleted of Langerhans cells responded to NA or MMF with strongly reduced flushing, indicating the importance of this cell type in the flushing response (Benyó et al., 2006; Carballo-Jane et al., 2007; Hanson et al., 2010). Mice with cell type specific depletion of HCA2 in either Langerhans cells or keratinocytes enabled the definition of the contribution of these cell types to the flushing phenomenon. Depletion of HCA2 in Langerhans cells abrogated the first phase and depletion of HCA2 in keratinocytes abrogated the second, longer lasting phase (Hanson et al., 2010). 3.3. Prostaglandins and cyclooxygenase Soon after NA was introduced into clinical practice to treat dyslipidemia, several hypotheses regarding the mechanism of NA-induced skin flushing were tested. It was known that vasodilatory prostanoids by themselves were able to elicit a flushing reaction, and that flushing caused by other substances, such as chlorpropamide in combination with alcohol ingestion, could be decreased by cyclooxygenase (COX) inhibitors (Barnett et al., 1980). The hypothesis of an involvement of prostanoids in NA-induced flushing was further supported by animal studies (Andersson et al., 1977; Rohte et al., 1977). In the late seventies and early eighties, several investigators tested the prostanoid hypothesis in humans, and showed that inhibition of the prostanoid production by indomethacin significantly reduced the NA-induced flushing reaction (Kaijser et al., 1979; Phillips & Lightman, 1981). The direct relationship of NA and prostanoids was demonstrated by of an increased PGD2 and PGE2 production after NA intake (Nozaki et al., 1987; Morrow et al., 1989). Although the cutaneous origin of the mediators responsible for the phenomenon was postulated as early as 1940 (Bean & Spies, 1940), experimental evidence that prostaglandins were produced in the skin following NA intake came much later (Morrow et al., 1992). More recently, several studies showed that PGE2, PGD2, keratinocytes and Langerhans cells were involved and required to elicit a complete flushing response in mice (Benyó et al., 2005; Benyó et al., 2006; Cheng et al., 2006; Maciejewski-Lenoir et al., 2006; Hanson et al., 2010). Langerhans cells and keratinocytes contribute differentially to the synthesis of specific prostanoids. The production of PGD2 is restricted to Langerhans cells while keratinocytes are the major source of PGE2 (Maciejewski-Lenoir et al., 2006; Hanson et al., 2010). Indirect evidence suggest that Langerhans cells, in addition to PGD2, may also produce PGE2. Mice lacking DP1, EP2 or EP4 receptors all reduce the intensity but do not abolish the first phase of the flushing response. This phase is dependent on the expression of HCA2 in Langerhans cells, which indicates that PGE2 is produced in epidermal Langerhans cells in response to NA (Benyó et al., 2005). Consistent with this, Langerhans cells express PGE2 synthase in addition to PGD2 synthase (Benyó et al., 2005; Benyó et al., 2006). Nevertheless, while Langerhans cells have been shown to in response to NA (Maciejewski-Lenoir et al., 2006), the secretion of PGE2 by Langerhans cells has yet to be demonstrated. Fig. 2 provides an overview of the cell types contributing to flushing in the anatomical context of the dermis and epidermis. Recently, some of the intracellular pathways underlying NA-induced prostanoid formation via HCA2 have been elucidated (Benyó et al., 2006; Walters et al., 2009; Hanson et al., 2010). According to the proposed model (Fig. 3), the immediate signaling pathway following the activation of HCA2 activates Gi-type G-proteins, which leads to an activation of the cytosolic phospholipase A2 (cPLA2), and the release of arachidonic acid from phospholipids in the cell membrane. It has also been reported that signaling of HCA2 in flushing involves β-arrestin 1, following phosphorylation of the receptor at its C-terminus, in response to agonist-induced receptor activation. Arrestins are a family of adaptor proteins that can bind

Fig. 2. Cross-section of the cutis and overview of flushing. HCA2 agonists in dermal blood circulation activate keratinocytes and Langerhans cells. Both cell types produce prostaglandins in response to HCA2 agonists that leads to vasodilation of dermal blood vessels.

to most GPCRs, inducing their internalization and thus playing a major role in their desensitization. Upon activation the receptor is phosphorylated by GPCR kinases (GRKs), which promote binding of β-arrestin, thus decreasing the signal. In addition, bound β-arrestin will recruit AP2 and clathrin thus facilitating the endocytosis via clathrin-coated pits. Furthermore, β-arrestins can mediate G-protein independent signaling, by serving as multiprotein scaffolds and bringing elements of specific signaling pathways into close proximity. β-Arrestin regulation has been demonstrated for numerous signaling networks, including the mitogen‐activated protein kinases ERK, JNK, and p38 as well as Akt, PI3 kinase, and RhoA (DeWire et al., 2007). Data from β-arrestin 1 deficient mice indicate that binding of NA to HCA2 in the epidermis, but not in adipocytes, initiates also non-G-protein mediated signaling and activation of cPLA2 through β-arrestin 1 (Walters et al., 2009). Thus, HCA2 may mediate cutaneous flushing in a β-arrestin1‐dependent fashion in contrast to the antilipolytic effect, which is not mediated by β-arrestin. This tissue specific signaling may also explain why patients taking NA experience a tolerance to flushing but not to the desired FFA lowering effect (Walters et al., 2009). Another explanation for this phenomenon could be that NA receptor desensitization differs depending on the cell type, or that there is a downregulation of receptors in cells of the epidermis whereas in adipose tissue the receptor surface receptor population remains. However, experimental evidence for this is lacking, and it appears more likely that tolerance to flushing develops due to desensitization of processes further downstream such as prostanoid formation and/or action. The release of arachidonic acid from phospholipids by cPLA2 is the first of several steps of prostanoid synthesis. Subsequently, arachidonic acid is converted by cyclooxygenase to prostaglandin H2, which is then processed to different prostanoids by specific prostanoid synthases. Cyclooxygenase exists in two major isoforms, COX-1 and COX-2. While COX-1 is expressed almost ubiquitously in a constitutive manner, COX-2 is usually seen as an inducible isoform that is involved in inflammatory processes. In humans, keratinocytes are among the few cell types that constitutively express COX-2 (Leong et al., 1996; Buckman et al., 1998), and COX-2 expression can be increased following UV

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A

B

Fig. 3. A, Biphasic flushing response following i.p. injection of HCA2 agonists in mice. An early phase of flushing becomes apparent following i.p. injection peaking at ~3 min and lasting for about 10 min. The subsequent late phase peaks around 25 min and is longer lasted than the first phase. The first phase of the flushing response is mediated by Langerhans cells and the second phase by keratinocytes. B, Signaling pathways regulated through HCA2 in Langerhans cells and keratinocytes (differences are highlighted by color). Agonists activate HCA2 both in Langerhans cells as well as keratinocytes. Both cell types have been shown to respond with calcium transients that are likely induced by inositol-1,4,5-triphosphate produced by phospholipase Cβ (PLCβ) activated by G-protein βγ-subunits. Ca2+-sensitive phospholipase A2 (PLA2) releases arachidonic acid (AA) in both cells, however there are differences in the downstream mechanisms of prostaglandin synthesis. Langerhans cells utilize cyclooxygenase-1 (COX-1) and keratinocytes cyclooxygenase-2 (COX-2) for generation of prostaglandin G2/H2 (PGG2/H2). Langerhans cells express prostaglandin D2 (PGD2) as well as prostaglandin E2 (PGE2) synthases and hence, secrete both E2 and D2 prostaglandins. In contrast, keratinocytes express only PGE2 synthase (PGE2 synth.) and secrete PGE2. Secreted prostaglandins diffuse toward dermal blood vessels were the G-protein coupled receptors DP1 and EP2/4 are activated by PGD2 and PGE2 respectively leading to cAMP mediated vaso-dilation.

light exposure (Buckman et al., 1998). Controversial data exist regarding COX-2 expression in mouse keratinocytes. While no constitutive expression was detected in keratinocytes from hairless mice, they expressed COX-2 when treated with a skin irritant (Leong et al., 1996). However, constitutive COX-2 expression in keratinocytes of C57BL6 mice using COX-2−/− mice as a negative control was recently reported (Hanson et al., 2010). COX-2 is preferentially coupled to PGE2 synthase and hence production of PGE2 (Brock et al., 1999). The physiological role of the constitutive expression and the regulation of COX-2 in keratinocytes remain elusive, although an auto- and paracrine regulatory role for growth and differentiation involving PGE2 has been proposed (Pentland & Needleman, 1986). On the other side, Langerhans cells are devoid of COX-2 under basal conditions (Hanson et al., 2010). Interestingly, the two phases of the NA and FAE-induced flushing can be attributed to different cells as well as different COX isoforms. The first phase of flushing is mediated by Langerhans cells and involves COX-1 while the second phase is mediated by keratinocytes and involves COX-2 (Hanson et al., 2010). Fig. 3 links the temporal phases of

flushing to a detailed model of the mechanism of flushing at a cellular and molecular level. 4. HCA2 and psoriasis The exact mechanism by which FAE induce anti-psoriatic effects is not known, and there may be multiple effects leading to the improvement of psoriatic lesions. Psoriasis is regarded as an organ-specific autoimmune disorder, with an inflammatory component, characterized by T-cell activation, infiltrates of monocytes, and also by hyperproliferation and incomplete differentiation of keratinocytes (Lowes et al., 2007). In humans, FAE have significant impact on systemic leukocyte numbers, in particular T-cells (Hoxtermann et al., 1998). In addition, FAE have been shown to have numerous cellular effects that might account for their anti-psoriatic effects, such as apoptosis induction, cytokine secretion, regulation of cellular redox systems, adhesion molecule expression, inhibition of angiogenesis and NFκB activity (Mrowietz & Asadullah, 2005; Garcia-Caballero et al., 2011; Meissner et al., 2011). More recently, it

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was proposed that DMF could improve psoriasis through induction of type II dendritic cells (Ghoreschi et al., 2011). The discovery that MMF is a HCA2 agonist raised the question whether HCA2 is involved in the anti-psoriatic effect of FAE (Tang et al., 2008). In support of this, expression of HCA2 was found to be up-regulated in the skin of psoriatic patients (Tang et al., 2008). FAE have already earlier been shown to elicit an intracellular calcium mobilization and to inhibit proliferation of cultured keratinocytes, thus providing a rationale for a potential involvement of HCA2 in the therapeutic effect (Thio et al., 1994). Since NA is able to induce HCA2-dependent calcium transients in keratinocytes (Hanson et al., 2010), it is likely that the calcium transients elicited by fumaric acid derivates are also mediated through HCA2, although this has never been experimentally demonstrated. Activation of HCA2 by MMF on keratinocytes would increase the release of PGE2, a known inducer of differentiation through intracellular Ca2+ increase and a positive autoregulatory feedback loop resulting in the induction of COX-2 expression (Evans et al., 1993; Watabe et al., 1993; Nantel et al., 1999). Interestingly, HCA2 has recently been proposed to play a role in skin physiology and keratinocyte differentiation (Bermudez et al., 2011). Nevertheless and in contradiction to observations mentioned above, PGE2 concentrations are already increased in the psoriatic epidermis (Hammarstrom et al., 1975; Reilly et al., 2000). Thus, the precise interplay between MMF, HCA2, COX-2 and PGE2 in keratinocytes and in the context of psoriasis demands further experimental investigation. Another possibility is that the effects of MMF on keratinocytes might be of little significance for the anti-psoriatic effects. Instead, MMF might primarily have an effect on HCA2 expressed by Langerhans cells or other immune cells, which then secondarily affects keratinocyte function in psoriasis. In this respect, it is of interest that HCA2 is highly expressed in monocytes/macrophages and neutrophils (Carballo-Jane et al., 2007), which are enriched in the psoriatic skin (Nickoloff & Nestle, 2004) and that the HCA2 agonist has recently been shown to exert anti-inflammatory effects (Wu et al., 2010; Lukasova et al., 2011b). 5. Physiological role of HCA2 in Langerhans cells and keratinocytes The physiological role of HCA2 functionally expressed in both Langerhans cells and keratinocytes is still elusive. A recent study has proposed a physiological role in skin homeostasis and keratinocyte differentiation for HCA2 (Bermudez et al., 2011). In addition, HCA2 may mediate prostanoid formation in response to epidermal trauma. For instance, the cutaneous reaction to excessive UV light exposure resembles HCA2-mediated flushing in some features like vasodilation and the burning sensation. Similar to flushing, keratinocytes release PGE2 following UV light exposure (Black et al., 1980; Ruzicka et al., 1983), in a COX-2 dependent manner (Buckman et al., 1998). Nevertheless, it is currently not clear how UV light induces COX-2 activation in keratinocytes. Theoretically, the formation of an agonistic HCA2 ligand in response to UV light could contribute to the epidermal response to UV light. In addition, there may be unknown ligands of HCA2 or unknown mechanisms that increase prostanoid production via HCA2 that are involved in skin inflammation following epidermal damage. Furthermore, the regulation of dermal blood perfusion via HCA2 expressed by epidermal cells may be a physiological process under certain conditions. For example, many skin alterations go along with localized erythema and could reflect a physiological regulation driven either by Langerhans cells, keratinocytes, or both, and involving mechanisms similar to those induced by HCA2 agonists in the skin. 6. Strategies to mitigate nicotinic acid-induced cutaneous effects Ever since NA has shown efficacy in the treatment of dyslipidemia independently of its flushing side effect (Kaijser et al., 1979), strategies have been developed to prevent or reduce flushing in order to increase tolerability. These strategies have targeted the pharmacokinetics of NA,

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inhibiting downstream signaling (prostanoid synthesis and/or prostanoid receptor blockade) or designing alternative ligands for HCA2. Soon after the discovery that prostaglandins were involved in NA-induced flushing, COX inhibitors such as acetylsalicylic acid (325 mg) or indomethacin (200 mg) were given 30–60 min prior to NA to prevent flushing (Jacobson, 2010). However, daily use of acetylsalicylic acid and/or other non-steroidal anti-inflammatory drugs may cause gastrointestinal bleeding and other side effects, which limit this approach. Since PGD2 was previously regarded as the main prostaglandin in NA-induced vasodilation, a direct antagonist of DP1 was developed to suppress flushing (Lai et al., 2007). The selective PGD2 receptor (DP1) antagonist, laropiprant (Paolini et al., 2008) has been approved in Europe as a combination with NA (Tredaptive®). Although the strategies described above significantly reduce the severity of flushing, none of them completely abolishes the flush (Jacobson, 2010). A possible explanation is that these strategies do not fully inhibit COX-2- and PGE2‐dependent processes. Laropiprant does not inhibit PGE2-mediated vasodilation and since most COX inhibitors do not inhibit COX-2 (Dishy et al., 2009). Other non-pharmacological methods proposed to reduce the side effect, or at least to increase the tolerability, include the administration of NA before bedtime and with a snack, and/or during meals (Jacobson, 2010). The use of extended-release formulation of NA has also been shown to reduce treatment discontinuation due to flushing (Morgan et al., 1996; Knopp et al., 1998). Different signaling mechanisms of HCA2 in adipocytes and cells mediating flushing have been the basis for the development of agonists with functional selectivity or biased agonism (Kelly et al., 2008; Walters et al., 2009; Smith et al., 2010). Ligands with biased agonism differently activate one of several downstream pathways of a receptor (Kenakin, 2011). Ideally, functionally selective agonists activate preferentially effectors linked to therapeutic effects while avoiding those involved in unwanted side effects. Novel HCA2 agonists that differentially activate downstream effectors have been developed (Richman et al., 2007). Specifically, the synthetic compound MK-0354, a partial agonist of HCA2, activate G-proteins but fails to induce ERK activation and internalization of the receptor and thus retains the antilipolytic effects while causing hardly any flushing (Lai et al., 2008; Semple et al., 2008). However, in clinical studies MK-0354 did not elevate HDL-cholesterol levels, and its further development has been stopped. Finally, it has been noted that the models used to assess the efficiency of flushing reduction in animals test only the vasodilatory component. It cannot be excluded that the sensory effects (dermal pain, itching or warmth) might be caused by another mechanism (Dunbar & Gelfand, 2010). For instance, Lai et al. (2007) observed that hyperemia was not correlated with some of the other symptoms, such as warmth, after 3 days of treatment in human subjects. It may be interesting to specifically address these questions and to explore the possibility that other pathways are involved in the sensory aspects of NA-induced skin effects. Furthermore, a point that warrants investigation is whether flushing represents an effect that is required for the efficacy of FAE regarding its anti-psoriatic effects. As we have mentioned above, it is not unlikely that prostanoids secreted upon MMF activation of HCA2 play a significant role in the beneficial effects on psoriasis. If this would be the case, the mitigation of flushing through inhibition of prostanoid formation or action could decrease the clinical efficacy of FAE preparations. An argument against this possibility would be that patients taking MMF experience, similarly to NA (Stern et al., 1991), a tolerance to flushing (Thio et al., 1995). However, the apparent anti-psoriatic activity appears to last for much longer time intervals (Thio et al., 1995). 7. Conclusions and future directions NA has been the first pharmacological agent shown to decrease cardiovascular mortality. Although later other drugs such as statins have

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supplanted NA as the first line treatment of dyslipidemia, it remains the most efficacious drug available to increase HDL-cholesterol plasma levels. Unfortunately, despite its beneficial effects, immediate release NA induces a flushing reaction in almost all patients, which impairs the adherence to the treatment. However, extended release formulations of NA have been developed that mitigate flushing to some degree. Extended release NA has also been combined with other strategies to further reduce flushing, such as COX-inhibition or DP1 antagonism. However, clinical efficacy with extended release NA with or without combination of other drugs still needs to be demonstrated. The recent prematurely stopped AIM-HIGH trial, which tested the effect of high dose versus low dose (placebo) NA combined with standard statin therapy has not shown any additional benefit in patients given high dose nicotinic acid (Boden et al., 2011). However, this clinical trial has been criticized for poor study design (Michos et al., 2012; Nicholls, 2012). The much larger endpoint study, HPS-2-THRIVE which is testing high-dose extended-release niacin in combination with the DP1 antagonist laropiprant, may provide more definitive conclusions (results expected 2013). Significant advances have been made during the last years regarding the understanding of the mechanisms underlying NA-induced skin effects. In particular, the discoveries of the involvement of HCA2 in both Langerhans cells and keratinocytes and the roles of PGD2 and PGE2 may lead to new approaches to mitigate NA-induced flushing. Regarding MMF and DMF, one of the main challenges is to understand the potential connection between HCA2 expressed in skin, the flushing reaction and the anti-psoriatic effects. If the activation of HCA2 in the skin is related to beneficial effects of MMF and DMF, this might lead to new approaches in drug treatment of psoriasis. Finally, it may be of interest to investigate whether MMF has effects on lipid metabolism and if NA has beneficial effects on psoriasis. There is only one small historical study on a potential benefit of NA treatment in psoriasis. In this study, 20 patients received low doses of NA for a relatively short time period, but the authors concluded that the beneficial effects observed would have also been expected in a population not treated with NA (Herrmann, 1964). Given the small size of the study group and the lack of a placebo group, the results are hard to interpret. Conflict of interest statement The authors declare no conflict of interest. Acknowledgments JH is a research associate of the Belgian Fédération Wallonie-Bruxelles “Fonds de la Recherche Scientifique” (F.R.S.-FNRS). References Aktories, K., Jakobs, K. H., & Schultz, G. (1980). Nicotinic acid inhibits adipocyte adenylate cyclase in a hormone‐like manner. FEBS Lett 115, 11–14. Altschul, R., Hoffer, A., & Stephen, J. D. (1955). Influence of nicotinic acid on serum cholesterol in man. Arch Biochem 54, 558–559. Andersson, R. G., Aberg, G., Brattsand, R., Ericsson, E., & Lundholm, L. (1977). Studies on the mechanism of flush induced by nicotinic acid. Acta Pharmacol Toxicol (Copenh) 41, 1–10. Barnett, A. H., Spiliopoulos, A. J., & Pyke, D. A. (1980). Blockade of chlorpropamidealcohol flushing by indomethacin suggests an association between prostaglandins and diabetic vascular complications. Lancet 2, 164–166. Bean, W., & Spies, T. (1940). A study of the effects of nicotinic acid and related pyridine and pyrazine compounds on the temperature of the skin of human beings. Am Heart J 20, 62–76. Benyó, Z., Gille, A., Bennett, C. L., Clausen, B. E., & Offermanns, S. (2006). Nicotinic acid-induced flushing is mediated by activation of epidermal Langerhans cells. Mol Pharmacol 70, 1844–1849. Benyó, Z., Gille, A., Kero, J., Csiky, M., Suchankova, M. C., Nusing, R. M., et al. (2005). GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. J Clin Invest 115, 3634–3640.

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