An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17

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An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17 Lynda Grine a,b, Lien Dejager a,b, Claude Libert a,b,1, Roosmarijn E. Vandenbroucke a,b,1,* a b

Inflammation Research Center, VIB, Ghent, Belgium Department Biomedical Molecular Biology, Ghent University, Ghent, Belgium

A R T I C L E I N F O

A B S T R A C T

Article history: Available online xxx

Psoriasis is a skin disease where various cytokines play a detrimental role, yet our understanding of the disease is still limited. TNF is a validated drug target in psoriasis and other autoimmune diseases, but its use is associated with side effects. Some paradoxical side effects of anti-TNF treatment are supposedly associated with type I IFNs, which are also implicated in the pathogenesis of psoriasis. Recently, the IL23/IL-17 axis has been associated with psoriasis as well, and new drugs targeting this axis have already been developed. Findings suggest that these cytokines are interwoven. We discuss recent findings reinforcing the role of TNF, Type I IFNs and IL-17 in the pathogenesis of psoriasis and the apparent inflammatory interplay between these three cytokines. ß 2014 Elsevier Ltd. All rights reserved.

Keywords: Psoriasis TNF Tumor necrosis factor Type I interferons IL-17/IL-23

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of TNF in psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of type I IFNs in psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Role of IL-23/IL-17 in psoriasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The interplay between TNF and type I IFNs in psoriasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. The interplay between TNF and IL-23/IL-17 in psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. The interplay between type I IFNs and IL-23/IL-17 in psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Conclusion: implications for the treatments of psoriasis and other diseases and current and future drugs. Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Psoriasis is a chronic inflammatory disease affecting 2–3% of the world population and is considered an immune-mediated inflammatory disease (IMIDs). The skin lesions are characterized by erythema, epidermal hyperplasia and scaling. Histological analysis reveals inflammatory infiltrates and capillary angiogenesis. Psoriasis has been extensively studied in the past, yet the

* Corresponding author at: Technologiepark, 927 9052 Ghent, Belgium. Tel.: +32 93313703. E-mail address: [email protected] (R.E. Vandenbroucke). 1 Both authors contributed equally.

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mechanism underlying the disease remains largely unknown. Genetic studies have revealed several susceptibility loci associated with psoriasis, but the pathology results from an intimate interplay between environmental factors and the immune cells of genetically susceptible individuals. There is no cure for psoriasis, but several treatments have been developed. Treatments depend on the severity of the disease as assessed by the Psoriasis Area Severity Index (PASI) score [1]. Clinicians usually start with a mild treatment, such as topical creams containing cortisones or use phototherapy, exposing the skin to certain types of ultraviolet (UV) light. These therapies can be combined to increase effectiveness. However, some patients require more drastic interventions, including drugs administered either orally or through injection. Non-biological drugs include

http://dx.doi.org/10.1016/j.cytogfr.2014.10.009 1359-6101/ß 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Grine L, et al. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.10.009

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methotrexate, cyclosporin and acitretin. Biological drugs have been developed over the past decade and approved for the treatment of various diseases, such as Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis and psoriasis. The most prescribed of these drugs are Tumor Necrosis Factor (TNF)-antagonists. The most popular TNF-antagonists are etanercept, infliximab and adalimumab, and two new anti-TNF drugs have been added to the list: certolizumab and golimumab. All these anti-TNF drugs behave differently in patients and in different diseases, making the choice of TNF-antagonist rather complex. If patients do not react well to one TNF-antagonist, clinicians often prescribe another a different one, although there are no specific guidelines for this. The widespread use of TNF-antagonists has validated TNF as a drug target, but their success has its limitations. As TNF also has immunoregulatory functions, long-term neutralization of TNF can be dangerous. Patients can become more susceptible to bacterial and fungal infections or at risk of reactivation of latent tuberculosis infection. Other adverse events include injection site reactions, infusion reactions, neutropenia, demyelinating disease, heart failure, cutaneous reactions, and malignancy [2–5]. Paradoxically, the use of anti-TNF drugs has also been associated with de novo induction of autoimmune diseases such as psoriasiform lesions and lupus erythematosus [6–9]. The most commonly observed side effect is the induction of cutaneous psoriasiform lesions in patients treated with TNF-antagonists for Crohn’s disease or rheumatoid arthritis. Studies suggest this effect is due to an imbalance between TNF and another cytokine: the type I interferons (type I IFNs). Type I IFNs are mainly known for their antiviral activity, but elaborate studies have shown their potency as immunoregulatory cytokines as well. The role of type I IFNs in autoimmune diseases is not entirely understood, but several observations suggest that they are involved with TNF in the development of autoimmunity. To overcome the pitfalls of TNF-antagonists, new biological agents have been developed, such as antibodies against Interleukin (IL)-17 and IL-12p40, both of which have been shown to play intricate roles in autoimmune diseases [10–14]. These antibodies are already in clinical trials or on the market, though their longterm use is yet to be evaluated. Psoriasis and other chronic inflammatory diseases seem to result from an overactive immune system, with TNF, type I IFNs and the IL-23/IL-17 axis playing interwoven roles. In this review, we discuss the intimate interplay between these cytokines in psoriasis and the insights that may be of potential value for future treatments for psoriasis. 2. Role of TNF in psoriasis TNF is a homotrimeric cytokine that is mainly produced by immune and epithelial cells. TNF can be membrane-bound and mediate cell–cell signaling, but it can also be cleaved by TACE/ ADAM17 and act as a soluble form. TNF exerts its functions by binding to two different receptors: TNFR1/p55 and TNFR2/p75. The latter is expressed solely on immune, endothelial and neuronal cells and is inducible, whereas TNFR1 is expressed ubiquitously and constitutively. TNF does not only induce inflammation by activating vascular endothelial cells and immune cells, but also acts as an important regulator of the development of lymphoid tissue by controlling apoptosis. Mice deficient in TNF do not develop germinal centers, similarly to TNFR1-deficient mice [15,16]. Increased levels of TNF are found at the sites of inflammation in several autoimmune diseases and upon neutralization, inflammatory symptoms are generally reduced. This led to the rationale of blocking TNF in patients suffering from autoimmune diseases that are associated with excessive amounts of TNF. Higher levels of TNF, TNFR1 and TNFR2 are observed in psoriatic lesions [17–20]. Keratinocytes express TNFR1 and are thus responsive to TNF. Stimulation with TNF

induces not only immune and inflammatory responses orchestrated by keratinocytes but also tissue remodeling, cell motility, cell cycling, and apoptosis [21]. Additionally, activated keratinocytes also produce many chemokines responsible for recruitment of neutrophils, macrophages and skin-specific memory T cells [21]. TNF is produced by a variety of cells involved in the pathophysiology of psoriasis, such as keratinocytes, dendritic cells (DCs), and NKT, Th1, Th17 and Th22 cells. This implies that TNF might be involved in both the initial phase and the chronic phase of psoriasis. Therefore, neutralization of TNF can affect several stages of the disease by interfering with the activation of different cell subtypes. Although TNF-antagonists are extensively prescribed to patients, the exact mechanism underlying psoriasis is not completely understood and the precise role of TNF is yet to be elucidated. One plausible mechanism is exaggerated TNF signaling, possibly due to genetic polymorphism in predisposed individuals. A recent meta-analysis by Zhuang et al. revealed a significantly decreased risk of psoriasis for the TNF 308G/A polymorphism and an increased risk for TNF 238G/A [22]. These single nucleotide polymorphisms (SNPs) can influence the transcription and regulation of TNF and other susceptibility genes, such as STAT4, IL-10 and vitamin receptor D (VDR). However, that study has some limitations, such as relatively small sample size and lack of adjusted estimates. Further research should investigate gene–gene interactions. In addition, evidence also indicates that TNFAIP3/ A20 affects the response to anti-TNF treatment. A20 can limit NFkB-mediated inflammation. A positive response to etanercept was found mostly in populations carrying two copies of the allele with the G allele of SNP rs610604 located in the TNFAIP3 gene [23]. This information could help clinicians to make an informed decision to select the appropriate TNF antagonist therapy. The past years, new sets of cytokines have been added to the pathophysiology of psoriasis, expanding our view of an already complex disease. New players such as IL-19, IL-20, IL-22 and IL-24 have also been implicated in psoriasis [24–26]. It has also been postulated that TNF might be involved in the induction of these cytokines. For example, the group of Haase used a murine spontaneous psoriasis model to unravel the role of TNF in the induction of IL-24 [27]. Transgenic expression of this cytokine was sufficient to induce skin inflammation, and upregulated levels of IL-24 were found in psoriatic epidermis [28,29]. Using K14-Cre IKK2fl/fl deficient mice, He and Liang found that early induction of IL-24 depends on TNF. The authors suggested that IL-24 is required for the initiation phase of psoriasis and that this early event depends on TNF/TNFR1 signaling [27]. The mechanism underlying the pathogenesis of psoriasis is still under study. The disease picture is becoming increasingly complex, but it is clear that TNF is involved in many processes of psoriasis. 2.1. Role of type I IFNs in psoriasis Type I interferons are well known for their antiviral effects, which were first described in 1957 by Isaacs and Lindemann as a factor interfering with viral infections [30]. They are part of the superfamily of interferons and consist of type I, II and III interferons. In humans there are 13 genes for IFNalpha (IFNa) and single genes for IFNbeta (IFNb), IFNepsilon, IFNkappa and IFNomega. They signal through a heterodimeric complex composed of IFNAR1 and IFNAR2. Over the last decades, increasing insight into their antiviral mechanisms have led to the use of type I IFN as a therapy for viral infections such as Hepatitis B and C [31,32]. Although the antiviral activities of interferons form an interesting topic, this review will not focus on this activity. Type I IFNs have also been implicated in the response to bacterial infections, inflammasome activation, intestinal homeostasis, cancer and in inflammatory and autoimmune diseases such as

Please cite this article in press as: Grine L, et al. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.10.009

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coeliac disease, Crohn’s disease and multiple sclerosis. Type I IFNs are thought to play a major role in the pathogenesis of psoriasis as well. Patients treated with IFNb and IFNa for multiple sclerosis or hepatitis C, respectively, have reported de novo induction or exacerbation of pre-existing psoriasis [33]. Afshar et al. studied all published cases of hepatitis C patients who developed psoriasis during IFNa treatment. They reported on 36 cases who suffered from de novo development or aggravation of pre-existing psoriasis [34]. Upon discontinuation of IFNa therapy, 93% of the patients reported resolution of the cutaneous disease. Moreover, Nestle et al. showed that IFNa drives the development of full-blown T-cell dependent psoriasis. They used a mouse xenograft model in which plasmacytoid dendritic cells (pDCs) infiltrate the skin very early and, once activated, produce immense amounts of IFNa [35]. Blocking IFNa activity with an antibody directed against IFNAR2 prevented the development of psoriasis. In addition, genetic studies revealed two genes of risk for psoriasis that are associated with type I IFNs: DDX58 and RNF114. Both are involved in sensing viruses and the subsequent induction of type I IFNs [36,37]. Additional studies on the role of type I IFNs in the pathophysiology of psoriasis found additional evidence. IFN regulatory factor-2 (IRF-2) is a transcriptional inhibitor of type I IFN signaling. Mice lacking this gene have higher expression levels of type I IFN-inducible genes and develop an inflammatory skin phenotype that strongly resembles psoriasis, suggesting that excessive type I IFN signaling is sufficient to induce a psoriasis-like phenotype [38]. However, results from basic science studies on the role of type I IFNs are contradictory. Since Van der Fits described imiquimod as a valid inducible experimental model for psoriasis in mice, many research groups have used this model to investigate the molecular basis of psoriasis [39]. Imiquimod (IMQ) is a TLR7 agonist that activates pDCs and thus acts as a potent inducer of type I IFNs. Daily application of imiquimod is sufficient to induce a psoriasis-like phenotype in mice. Aldara cream containing 5% IMQ is used against basal cell carcinomas and genital warts and can indeed induce psoriasis in patients as a side effect. The role of type I IFNs in IMQ-induced psoriasis has also been studied in IFNAR1deficient mice using the imiquimod model. Two studies suggest that IMQ-induced skin lesions are independent from type I IFN signaling [40,41]. Mice lacking IFNAR1 were not protected from IMQ-induced psoriasis, although they produced less IFNa, IL-6 and IL-22 while IL-17A levels were not affected. Also, it has been shown that IFNa can act in synergy with imiquimod to mediate inflammation. Imiquimod alone is a weak inducer of IL-23, IL-6, and TNF, but upon simultaneous stimulation with IFNa, induction is far stronger [42]. The authors showed that IFNa increases TLR7 levels, sensitizing the environment to TLR7 agonists. They explained the discrepancy about the role of IFNa in psoriasis by pointing out that Aldara contains various components that can act independently from TLR7 and IFNAR1. These observations support a role for type I IFN signaling in this chronic skin disease, leading to the concept of blocking these cytokines as well. Indeed, the company MedImmune conducted a phase I trial on patients with psoriasis to investigate the effects of MEDI-545, an anti-IFNa monoclonal antibody [43]. In this trial, they evaluated the safety profile of the antibody, and its effect on the biological activity of IFNa in skin biopsies and on disease activity. Although the drug was found to be well tolerated and safe, MEDI-545 did not appear to affect the established psoriasis plaques in the subjects. The same antibody had already shown clinical benefit in a trial for systemic lupus erythematosus (SLE), another disease characterized by increased type I IFN activity. The authors ruled out that observed difference between the trials were due to antibody dose differences. However, the study focused only on IFNa though IFNb is upregulated in psoriatic lesions as well, and both ligands signal through the IFNAR1/IFNAR2 complex. Moreover, they only

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studied the effect of IFNa inhibition in established psoriatic plaques, whereas data suggests that type I IFNs mainly have a role in initiating psoriasis. They could only conclude that blocking IFNa with MEDI-545 is not sufficient to reduce type I IFNinducible genes in established psoriatic plaques. In conclusion, these observations support the initiating role of the type I IFNs in psoriasis. 2.2. Role of IL-23/IL-17 in psoriasis Over recent years, another set of cytokines has emerged as major players in various autoimmune diseases: the IL-23/IL-17 axis. These two cytokines characterize a subset of helper T cells called T-helper 17 (Th17), which play a major role in psoriasis and other inflammatory disorders. Psoriasis used to be regarded as a Th1-driven disease, but our understanding of the disease has greatly changed over the years and now it is regarded as a Th17 disease. Th17 cells are characterized by production of IL-17, IL21, and IL-22. They can produce TNF and IL-6 as well in response to certain stimuli [44]. Th17 cells differentiate from naive CD4+ T cells in the presence of TGF-b, IL-1b and IL-6. IL-23 was previously assumed to be essential for differentiation as well, but is now thought to stimulate survival and expansion of Th17 cells. The IL-17 cytokine family consists of six ligands: IL-17A, B, C, D, E and F. The most studied ligands are IL-17A and IL-17F. These can form homodimers and heterodimers, both of which signal through a common receptor subunit IL-17RA. IL-23 is mostly known for its important role in survival and expansion of these cells [45]. IL-23 shares a common subunit with IL-12, called IL-12p40, which forms a heterodimer with IL-23p19. IL-12 is a heterodimer of IL-12p40 and IL-12p35, which together form IL-12p70. IL-12 and IL-23 share a common receptor subunit, IL12Rb 1, which together with IL-23R forms the signaling receptor complex for IL-23. In psoriasis patients, the IL-23 pathway is activated and characterized by high level production of IL-23 by DCs and keratinocytes and increased numbers of Th17 cells [46]. Increased mRNA levels of IL-23p19 and IL-12p40, but not IL-12p35, have been detected in various studies, pointing to a specific role for IL-23 but not IL-12 [47]. Genetic association studies have revealed polymorphisms in the IL-12p40 and IL-23R genes that increase the risk of developing psoriasis. Other intriguing observations include the following: repeated intradermal injections of IL-23 are sufficient to induce acanthosis in skin, whereas mice lacking the IL-23p19 subunit do not develop full-blown psoriasis-like skin lesions upon treatment with imiquimod [39]. These mice also cannot induce IL-17A and IL-17F. Wohn and colleagues showed that the IL-23 produced by Langerin-negative conventional DCs is important for the development of psoriatic lesions in mice [41]. However, the initial rationale to target IL-23 was not based on these observations. High IL-12 and IL-23 levels were detected in psoriatic skin lesions, yet inhibition of only the p40 subunit improved clinical symptoms, whereas inhibition of IFNg, which is regarded as the key cytokine in IL-12/Th1 signaling, did not. Blocking IL-12p40 reduced Th1 cytokines and IL-12/IL-23 levels in psoriasis patients. Compared to healthy controls, psoriasis patients have higher levels of IL-17 in lesional skin and in peripheral circulation. The levels of IL-17 also correlate with disease severity. Several cell types other than Th17 cells can produce IL-17, including neutrophils, mast cells, macrophages, natural killer cells, dendritic cells and Tc17 cells (CD8+). Another type of cells, g d T cells, produces more IL-17 than Th17 cells. In fact, in the IMQ model, IL-17 producing g d T cells and RORgT+ innate lymphoid cells are necessary and sufficient to induce psoriatic plaques [48]. In the same setting, IL-17F plays a more prominent role

Please cite this article in press as: Grine L, et al. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.10.009

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than IL-17A. IL-17F-producing lymphocytes are found in higher numbers in IMQ-treated skin than IL-17A and IL-22 producing cells, and similarly, IL-17F-knockout mice showed significantly less inflammation compared to IL-17A-knockout mice. Although it is known that IL-17A and IL-17F differ in effects and in regulation, little is known about their distinct roles in human psoriasis. In Crohn’s disease, IL-17A and IL-17F play different roles. The latter is attributed solely a pathological role for driving inflammation, whereas the role of IL-17A is debated. Both proand anti-inflammatory effects have been reported for IL-17A in Crohn’s disease [11,49–51]. However, dual blockade of both ligands has been reported by Wedebye-Schmidt and colleagues as more effective than blockade of either cytokine alone in an experimental colitis model [50]. This might explain why secukinumab, a fully human monoclonal antibody against IL17A, provided almost no clinical benefit in patients with Crohn’s disease and was associated with an increased number of adverse events than the placebo. Until now, two monoclonal antibodies against IL-17A and one against IL-17RA have been evaluated in clinical trials for the treatment of psoriasis. Both secukinumab (Novartis) and ixekizumab (Lilly) target IL-17A, and brodalumab (Amgen) targets IL-17RA. Each antibody has been compared to etanercept and data from these trials are encouraging. Still, the question is whether it is best to target the ligand or the receptor. On the one hand, cytokines are readily accessible to the neutralizing antibodies in circulation, but receptors are expressed in tissues and might be inaccessible. On the other hand, most cytokine families consist of different ligands and these cytokines are often redundant. In the case of IL-17, specific inhibition of IL-17A may not be sufficient, as IL-17F remains active, so blocking the common receptor unit IL-17RA might be more effective. Yet another possibility is targeting IL-17A and IL17F simultaneously, which was explored by Genentech and NovImmune. RG7624 (Genentech) and NI-1401 (NovImmune) are both in clinical phase I trials [52]. Future studies will reveal the beneficial effects of targeting the IL-23/IL-17 axis in psoriasis and other IMIDs. 2.3. The interplay between TNF and type I IFNs in psoriasis Most nucleated cell expresses both TNFR1 and the type I IFN receptors and can thus respond to both cytokine families. The balance between TNF and type I IFNs is crucial for a healthy immune response. Initially, it seemed that TNF mainly regulated responses against bacterial insults whereas type I IFNs (and type II and III) were thought to function only as antiviral cytokines. Yet, elaborate studies revealed that neither cytokine is exclusively involved in eliciting inflammation in response to either bacterial or viral infection, but have more pleiotropic functions and that intensive crosstalk exists between both pathways. TNF can either induce or inhibit the production of type I IFNs. Yarilina et al. described how primary macrophages stimulated with TNF rapidly produced IRF1-mediated IFNb [53]. This induction was self-sustaining and acted in synergy with downstream effects of TNF. They also showed that in the presence of TNF, macrophages are primed and their responses to subsequent TLR78 and -9 stimulation are enhanced due to increased production of type I IFNs. Similar results were obtained in fibroblast-like synoviocytes from patients with rheumatoid arthritis [54]. Moreover, we showed that type I IFNs mediate some of the toxic effects of TNF by mediating tissue infiltration by white blood cells and cell death [55]. In these settings, TNF is responsible for the production of type I IFNs and both of them act in concert to enhance inflammation. In other conditions, TNF inhibits the production of type I IFNs by acting on the pDCs (Fig. 1). pDCs go through stages of maturation and TNF can accelerate this process. Activation and

Fig. 1. TNF and type I IFNs affect each other at the level of pDCs. TLR7-activated pDCs produce TNF and type I IFNs. Type I IFNs enhance their own production and of TNF, whereas TNF silences type I IFN production. Together with pDCs, they drive the inflammatory events in psoriasis.

maturation markers, such as CCR7, CD83 and HLA-DR, are increased when pDCs are treated with exogenous TNF [56]. Surprisingly, upon stimulation, pDCs produce both IFNa and TNF. TNF reaches a maximum before IFNa and forces pDCs to mature. Mature pDCs cease to produce IFNa. Neutralization of TNF sustains this IFNa production, suggesting that TNF is the sole actor in this negative feedback [57]. However, activated pDCs depend on IFNa for ongoing secretion of TNF, because blocking IFNAR1 decreases TNF levels. This crossregulation between TNF and IFNa with feedback loops is mediated by CD300a/c [58]. It has been postulated that neutralizing TNF by antibodies inhibits this maturation process and is responsible for excessive IFNa production, which could lead to de novo induction or exacerbation of pre-existing autoimmune diseases such as psoriasis [57,59]. The crosstalk between TNF and type I IFNs has also been postulated in sarcoidosis, rheumatoid arthritis, Crohn’s disease and systemic lupus erythematosus. These observations support the hypothesis depicted in Fig. 2: patients on anti-TNF drugs are more responsive to pDC-targeted stimuli such as wounds and infections and will produce excessive amounts of type I IFNs, inducing an exaggerated pro-inflammatory loop. Potential hazardous stimuli might come from the cutaneous microbiome, overactivating the immune system during wounds and infections in these patients. Researchers investigated the role of the skin microbiome in psoriasis patients, and the observations of Grice’ research group suggest an intimate interplay with the skin microbiome, which triggers the sensitized immune system in these patients, leading to psoriatic lesions (Fig. 2) [60–62]. Moreover, analysis of the cutaneous microbiome from non-responders to anti-TNF or from patients with a stronger ISRE signature would allow us to extrapolate the data from cytokine levels to the potential triggers residing on the skin of patients. Intriguingly, type I IFNs may also be regarded as prognostic markers for responsiveness toward anti-TNF drugs. Two studies investigated this matter for rheumatoid arthritis (RA). In 2010, Mavragani and colleagues studied the association between plasma type I IFN activity and the IFNb/a ratio. They found that this ratio, together with IL-1ra, could predict the therapeutic response to TNF antagonists [63]. The authors propose that increased IFNb levels in RA patients result in anti-proliferative effects that synergize with the anti-inflammatory effects of TNF inhibition, resulting in improved efficacy. Another study conducted by the group of Verweij investigated the type I IFN signature before and after treatment of RA patients with etanercept [64]. This treatment induced a significant increment of type I IFN-regulated genes in a subset of patients. Remarkably, these patients had a poor clinical outcome following etanercept treatment. It must be pointed out that in the first study the subjects were predominantly Hispanic and that both studies were performed on rather small patient populations. Yet, the results warrant repetition of the studies on a larger scale. If these results can be confirmed, it would be useful to measure type I IFN activity, IFNb/a ratio and type I IFN-regulated genes before any treatment to predict the patient’s response to treatment with anti-TNF drugs. Indeed, a new clinical study will

Please cite this article in press as: Grine L, et al. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.10.009

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Fig. 2. Skin of patients on anti-TNF may react differently during stress responses due to the silenced negative feedback of TNF on type I IFNs. In normal skin, pDCs are activated and produce TNF and type I IFNs. Type I IFNs can act on pDCs and stimulate their own production and of TNF (1), whereas TNF promotes pDC maturation and hereby silences production of type I IFN (2). Additional TLR7 agonists, possibly residing on the skin can trigger pDCs during stress responses, but this is strictly controlled; the inflammation resolves. This negative feedback by TNF is lost upon neutralization with TNF antagonists, where continuous presence of TLR7 agonists leads to uncontrolled type I IFNs production and subsequent development of psoriasis.

investigate whether there is a correlation between the improvement of psoriasis in patients receiving etanercept and the levels of TNF and type I IFNs [65]. This would allow clinicians to stratify psoriasis patients and prescribe anti-TNF drugs to those who are more likely to benefit from this type of treatment. 2.4. The interplay between TNF and IL-23/IL-17 in psoriasis TNF is a very potent cytokine: systemic injection of TNF can lead to lethal shock [55]. The effect of intradermal injection of recombinant TNF resembles the effect of extensive exposure to solar UV: ICAM-1, VCAM-1 and E-selectin are upregulated, the latter on dermal microvascular endothelial cells. CD44 is increased as well, which allows leukocytes to bind to the endothelial surfaces [66]. Intradermal injection of TNF also induces influx of neutrophils and lymphocytes, as well as migration of epidermal Langerhans cells (LCs) in a Caspase-1 dependent manner [67,68]. Repeated intradermal injection of IL17 results in edema, IL-1b production and neutrophil recruitment in the skin, partially mediated by Caspase-1 as well [69]. However, IL-17 is not always a potent trigger on its own. Maione et al. elegantly showed in two mouse models of inflammation that IL-17 can exert its pro-inflammatory functions only in a predisposed environment, but not on its own [70]. The main action of IL-17 here seems to be recruitment of neutrophils to the site of inflammation. Though IL-17 may seem a weak inducer, evidence suggests that it can enhance inflammation through synergy with TNF and IFNg. For example, IL-17 affects keratinocyte activation by IFNg. Upon treatment with IL-17, keratinocytes produce GMCSF in higher quantities than after stimulation with IFNg alone. However, combined treatment with IL-17 and IFNgamma reveals their synergistic effect in the production of GM-CSF [71]. Likewise, the production of CXCL1 by keratinocytes is enhanced by a combination of IL-17 and IFNg in comparison to treatment with either cytokine. Similar findings were observed with IL-4: GM-CSF and CXCL1 peaked when keratinocytes were treated with IL-17, IFNg and IL-4 simultaneously [67]. But as mentioned above, IL-17 can also synergize with TNF. The most frequently described event is their synergistic recruitment of neutrophils (Fig. 3), where both TNF and IL-17 induce CXCL1, CXCL2, CXCL5, IL-8, P-selectin and Eselectin [72–74]. In addition, both cytokines enhance the production of CCL20, MCP-1, MIP-2, S100A8 and b-defensin

3 synergistically [73,75–78]. S100A8 is induced by TNF not only in human keratinocytes and IL-17, but also in synovial tissue, indicating that the synergy between TNF and IL-17 exists in psoriasis, RA and possibly other diseases. The group of Krueger provided evidence that IL-17 and TNF cooperate to suppress melanogenesis in normal human melanocytes, and this was also observed in psoriatic skin, where both cytokines are overexpressed [73]. Psoriasis has indeed been associated with dysregulation of pigmentation: actively inflamed skin is often characterized by hypopigmentation, whereas resolved lesions develop hyperpigmentation. In order to understand the early combined actions of IL-17 and TNF, skin biopsies from healthy volunteers were used to make an elegant three-dimensional model, which they treated with IL-17 and TNF [79]. By adding both pivotal cytokines simultaneously, they mimicked the microenvironment of psoriasis and observed that the inner proliferative layer was inhibited early and that the occludin expression pattern was affected. Donetti et al. concluded that TNF and IL-17 have direct effects on the homeostasis of the epidermis. It is therefore not surprising that dual inhibition of TNF and IL-17 has already been proposed. Koenders and colleagues described how simultaneous inhibition of TNF and IL-17 greatly reduced symptoms in experimental arthritis [77]. This could also be a strategic therapy for psoriasis. Covagen has developed a bispecific inhibitor consisting of a traditional antibody against TNF and an IL-17A neutralizing Fynomer, a small binding protein derived from the human Fyn SH3 domain. This ‘‘FynomAb’’ recently entered phase IB/IIA trials for safety, tolerability and pharmacokinetics, as well as for improvement of psoriatic skin lesions and biological responses [80]. Altogether, the synergistic

Fig. 3. TNF and IL-17 synergize in the recruitment of neutrophils. Various cell types in psoriatic skin produce TNF and IL-17. TNF and IL-17 can stimulate neutrophil recruitment on their own, but also together in a synergistic manner, leading to enhanced inflammation.

Please cite this article in press as: Grine L, et al. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.10.009

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actions resulting from TNF and IL-17 signaling may represent an effective therapeutic target to treat psoriasis. 2.5. The interplay between type I IFNs and IL-23/IL-17 in psoriasis Both type I IFNs and IL-17 have been implicated in numerous autoimmune diseases, such as multiple sclerosis, Crohn’s disease, rheumatoid arthritis and psoriasis. In the literature, type I IFNs are mainly reported to limit IL-17 production, but a direct link between type I IFNs and IL-17 in psoriasis has not been described. In multiple sclerosis (MS), which is treated with IFNb, Th17 cells play a role additional to the role of Th1 cells. IL-17 mRNA and protein are increased in active MS brain lesions [81,82]. Elevated levels of IL-17 are also found in blood-derived mononuclear cells and cerebrospinal fluid of MS patients compared to healthy controls [83–85]. The widely used murine model of MS, experimental autoimmune encephalomyelitis (EAE), provides evidence for the proinflammatory role of IL-17 and IL-23, but the exact role of type I IFNs and IL-17 in MS is not entirely understood. Numerous studies postulated that the beneficial effect of IFNb therapy is the reduction of IL-17 levels. Both IL-10 and IL27 have been reported to inhibit IL-17 [86,87]. Dendritic cells stimulated with IFNb, produce IL-10, IL-27 and IL-12p35, which is mediated by elevated TLR7 levels. IFNb also blocks IL-1b, TGFb, IL23 and IL-12p40, thereby inhibiting in vitro and in vivo Th17 differentiation [88,89]. But conflicting results suggest that the mechanism of IFNb treatment is much more complex. In a Th1driven EAE model, administration of IFNb was protective as expected, but when Th17 cells mediated the disease, treatment with IFNb aggravated the symptoms [90]. Similarly, patients suffering from relapsing-remitting MS (RRMS) do not always respond to IFNb. In a study conducted by Ba˘las¸a et al., 37.5% of the patients were non-responders and had significantly increased serum IL-17A levels in comparison to the responders, whereas Axtell et al. described heightened levels of IL-17F in those who did not respond to IFNb [91]. In contrast to MS, no direct link between type I IFNs and IL-17 in psoriasis has been described so far, although both cytokines are reduced in psoriatic skin lesions of patients treated with narrow band UV-B suggesting they act in concert in psoriasis [92]. During skin injury, pDCs are activated by the release of nucleic acids and produce IFNa in response, which promotes epidermal regeneration and wound healing. During this process, IL-17 and IL-22 are produced as well and it has been shown that depletion of pDCs impairs the production of these cytokines. Similar effects were observed in IFNAR1 KO mice and this was accompanied by a delay in wound reepithelization, which suggests that type I IFNs drive the differentiation of IL-17- and IL-22-producing T cells during wound repair [93]. IL-22, a member of the IL-10 family has also been implicated in MS and psoriasis, and is often associated with the Th17 axis. It signals through a heterodimeric receptor complex consisting of IL-10R2 and IL-22R and induces several genes in keratinocytes such as b defensins and S100 family proteins, both antimicrobial proteins that are implicated in psoriasis. Moreover, IL-22 stimulates thickening of the epidermis via inhibition of terminal keratinocyte differentiation through IL-22R. Expression of IL-22R is enhanced when keratinocytes are treated with IFNa, resulting in increased phosphorylation of STAT3 and increased IL-22 signaling [94]. This suggests that elevated type I IFNs may act indirectly on keratinocytes through IL-17 and IL-22R signaling (Fig. 4). IL-17 and IL-22 have been reported to act in synergy and can enhance skin inflammation together [25,69,95]. In wound healing, IL-17/IL-22 signaling is silenced toward the end, blocking keratinocyte migration, proliferation and antimicrobial protein production. Sustained type I IFNs activity will impair

Fig. 4. IL-17 and type I IFNs can act on the skin directly and indirectly, respectively. IL-17 can act directly on keratinocytes, but also indirectly through upregulation of IL-22R. Type I IFNs can affect expression levels of IL-17 and can also stimulate IL22R expression, hereby acting indirectly on keratinocytes.

this shutdown and lead to the development of psoriatic lesions [93,94,96]. However, Christophers et al. suggested that immune activation by type I IFNs and IL-17 is bimodal in psoriasis: TLR activation and IL-1 secretion by keratinocytes activate and recruit dendritic cells, including pDCs [97]. Subsequently, polymorphonuclear neutrophils and IL-17 producing cells are recruited. In this phase, driven by IL-17, pDCs secrete large amounts of IFNa, skewing the immune axis toward the classical Th1-mediated immune response. Type I IFNs and IL-17 can act in concert. This is elegantly illustrated in an autoimmune model in which BXD2 mice develop glomerulonephritis, proteinuria, splenomegaly, and autoantibody production. These mice exhibit increased levels of both IL-17 and type I IFNs, and studies have revealed that type I IFN signaling and antibody production are augmented by IL-17 [98]. In conclusion, both cytokines have been studied separately in psoriasis, yet the interaction between type I IFNs and IL-17 may be relevant for new therapies and thus poses an interesting field of investigation. 3. Conclusion: implications for the treatments of psoriasis and other diseases and current and future drugs An increasing number of inflammatory diseases are being associated with excessive TNF, type I IFNs and IL-23/IL-17 signaling. Anti-TNF drugs, as well as IFNa and IFNb, are effective therapies for autoimmune diseases and viral infections, respectively, but their side effects of de novo induction of diseases such as psoriasis and lupus have driven research to find novel drug targets. Today, many clinicians focus on the use of drugs targeting the IL23/IL-17 axis by neutralizing IL-17A, IL-17F, IL-17R, IL23p19 and IL-12p40. However, as we point out, the triangular interplay between TNF, type I IFNs and IL-17 is of great importance and targeting one of them may affect the others. The three cytokines seem to be the cornerstones of an inflammatory triangle that plays a central role in the development and maintenance of psoriasis and other chronic inflammatory diseases (Fig. 5). The cross regulation between TNF and type I IFNs is quite complex, but it seems to depend on the microenvironment. TNF can induce IRF-1 mediated production of type I IFNs in macrophages [53], but can also act via TNFR1 as a negative regulator of IFNa production in pDCs [56,57,59]. In turn, type I IFNs can mediate inflammatory responses elicited by TNF and can also act as an enhancer for TNF production by pDCs, thereby indirectly stimulating its own shutdown [58]. In psoriasis, the exact interplay is not entirely understood at the molecular level, but it is clear that targeting TNF only is not always sufficient. Neutralization of TNF results in loss of controlled type I IFN signaling and leads to increased IFNa secretion and de novo induction of psoriasis or aggravation of the pre-existing condition. It seems that pDCs are the central cell population in this cross regulation. On the other hand, TNF also interacts with the IL-23/IL-17 axis, resulting in synergistic recruitment and activation of neutrophils. It is therefore not surprising that certain polymorphisms in the IL-23R gene can affect a patient’s response to anti-TNF agents [99]. Unfortunately, the interaction between type I IFNs and the IL-23/IL-17 axis have

Please cite this article in press as: Grine L, et al. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.10.009

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7

References

Fig. 5. The inflammatory triangle of TNF, type I IFNs and IL-17 in psoriasis. Overactivation of TNF can lead to inflammation, but it can also synergize with IL-17 by enhancing neutrophil recruitment. IL-17 also mediates psoriatic inflammation directly and indirectly by acting on keratinocytes. pDC-derived type I IFNs initiate psoriasis (full arrow) and is normally silenced by TNF, which is lost during anti-TNF treatments (dotted arrows). Type I IFNs can act on keratinocytes indirectly together with IL-17 through increase of IL-22R. Thick arrows indicate synergy.

remained largely understudied, although their interplay in MS has been described. Type I IFNs might act in a normal immune system mainly by suppressing the Th17 arm of the immune system. However, it is plausible that type I IFNs and IL-17 may act in concert in a bimodal manner to enhance auto-inflammation, but this has yet to be investigated. Based on the observations described above, patients with psoriasis may be stratified into populations, based mainly on whether the psoriasis is mediated by IL-17, TNF or type I IFNs, and diagnosed according to the inflammatory triangle depicted in Fig. 5. This inflammatory triangle implies that in order to achieve maximal therapeutic efficacy, one corner could be used to predict a patient’s outcome in a therapy targeting another corner, or whether blocking two corners of the triangle could result in greater clinical benefits. In the case of anti-TNF therapy, patients who are prone to an increased type I IFN response and development of psoriatic lesions could benefit from simultaneous inhibition of this pathway by blocking IFNAR1. Likewise, patients suffering from psoriasis due to synergy between TNF and IL-17 can be treated by simultaneous inhibition of both TNF and IL-17, which may result in synergistic clearance of symptoms. In an era where personalized medicine is coming closer, this kind of insights can take us a step closer to substantially treat patients suffering from psoriasis and other IMIDs. Acknowledgments This work was funded by the Agency for Innovation by Science and Technology (IWT), (101190), the Research Foundation Flanders (FWO Vlaanderen), (1220613N and 12C8512N) and the Interuniversity Attraction Poles Program of the Belgian Science Policy (IUAP), (VII-32). We would like to thank Amin Bredan for manuscript editing.

[1] Fredriksson T, Pettersson U. Severe psoriasis – oral therapy with a new retinoid. Dermatologica 1978;157(4):238–44. [2] Moustou A-E, Matekovits A, Dessinioti C, Antoniou C, Sfikakis PP, Stratigos AJ. Cutaneous side effects of anti-tumor necrosis factor biologic therapy: a clinical review. J Am Acad Dermatol 2009;61(3):486–504. http://dx.doi.org/10.1016/ j.jaad.2008.10.060. [3] Antoni C, Braun J. Side effects of anti-TNF therapy: current knowledge. Clin Exp Rheumatol 2002;20:S152–7 (6 Suppl 28):. [4] Balakumar P, Singh M. Anti-tumour necrosis factor-alpha therapy in heart failure: future directions. Basic Clin Pharmacol Toxicol 2006;99(6):391–7. http://dx.doi.org/10.1111/j.1742-7843.2006.pto_508.x. [5] Kerbleski JF, Gottlieb AB. Dermatological complications and safety of anti-TNF treatments. Gut 2009;58(8):1033–9. http://dx.doi.org/10.1136/gut.2008.163683. [6] Almoallim H, Al-Ghamdi Y, Almaghrabi H, Alyasi O. Anti-tumor necrosis factor-a induced systemic lupus erythematosus. Open Rheumatol J 2012;6:315–9. http://dx.doi.org/10.2174/1874312901206010315. [7] Debandt M, Vittecoq O, Descamps V, Le Loe¨t X, Meyer O. Anti-TNF-alphainduced systemic lupus syndrome. Clin Rheumatol 2003;22(1):56–61. http:// dx.doi.org/10.1007/s10067-002-0654-5. [8] Iborra M, Beltra´n B, Bastida G, Aguas M, Nos P. Infliximab and adalimumabinduced psoriasis in Crohn’s disease: a paradoxical side effect. J Crohns Colitis 2011;5(2):157–61. http://dx.doi.org/10.1016/j.crohns.2010.11.001. [9] Barthel C, Biedermann L, Frei P, Vavricka SR, Ku¨ndig T, Fried M, et al. Induction or exacerbation of psoriasis in patients with Crohn’s disease under treatment with anti-TNF antibodies. Digestion 2014;89(3):209–15. http://dx.doi.org/ 10.1159/000358288. [10] Paradowska-Gorycka A, Wojtecka-Lukasik E, Trefler J, Wojciechowska B, Lacki JK, Maslinski S. Association between IL-17F gene polymorphisms and susceptibility to and severity of rheumatoid arthritis (RA). Scand J Immunol 2010;72(2):134–41. http://dx.doi.org/10.1111/j.1365-3083.2010.02411.x. [11] Seiderer J, Elben I, Diegelmann J, Glas J, Stallhofer J, Tillack C, et al. Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn’s disease and analysis of the IL17F p.His161Arg polymorphism in IBD. Inflamm Bowel Dis 2008;14(4):437–45. http://dx.doi.org/10.1002/ibd.20339. [12] Spadaro A, Lubrano E. Beyond anti-TNF-a agents in psoriatic arthritis. Expert Rev Clin Immunol 2013;9(6):507–9. http://dx.doi.org/10.1586/eci.13.32. [13] Clarke AW, Poulton L, Wai HY, Walker SA, Victor SD, Domagala T, et al. A novel class of anti-IL-12p40 antibodies: potent neutralization via inhibition of IL-12IL-12Rb2 and IL-23-IL-23R. MAbs 2010;2(5):539–49. http://dx.doi.org/ 10.4161/mabs.2.5.13081. [14] Toichi E, Torres G, McCormick TS, Chang T, Mascelli MA, Kauffman CL, et al. An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL12/IL-23 in psoriasis. J Immunol 2006;177(7):4917–26. [15] Pasparakis M, Alexopoulou L, Episkopou V, Kollias G. Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J Exp Med 1996;184(4):1397–411. [16] Le Hir M, Bluethmann H, Kosco-Vilbois MH, Mu¨ller M, di Padova F, Moore M, et al. Tumor necrosis factor receptor-1 signaling is required for differentiation of follicular dendritic cells, germinal center formation, and full antibody responses. J Inflamm 1995–1996;47(1–2):76–80. [17] Ettehadi P, Greaves MW, Wallach D, Aderka D, Camp RD. Elevated tumour necrosis factor-alpha (TNF-alpha) biological activity in psoriatic skin lesions. Clin Exp Immunol 1994;96(1):146–51. [18] Lew W, Bowcock AM, Krueger JG. Psoriasis vulgaris: cutaneous lymphoid tissue supports T-cell activation and ‘‘Type 1’’ inflammatory gene expression. Trends Immunol 2004;25(6):295–305. http://dx.doi.org/10.1016/j.it.03.006. [19] Bonifati C, Ameglio F. Cytokines in psoriasis. Int J Dermatol 1999;38(4): 241–51. [20] Kristensen M, Chu CQ, Eedy DJ, Feldmann M, Brennan FM, Breathnach SM. Localization of tumour necrosis factor-alpha (TNF-alpha) and its receptors in normal and psoriatic skin: epidermal cells express the 55-kD but not the 75kD TNF receptor. Clin Exp Immunol 1993;94(2):354–62. [21] Banno T, Gazel A, Blumenberg M. Effects of tumor necrosis factor-alpha (TNF alpha) in epidermal keratinocytes revealed using global transcriptional profiling. J Biol Chem 2004;279(31):32633–42. http://dx.doi.org/10.1074/ jbc.M0.40064220. [22] Zhuang L, Ma W, Cai D, Zhong H, Sun Q. In: Novelli G, editor. Associations between tumor necrosis factor-a polymorphisms and risk of psoriasis: a meta-analysis. Public Library of Science; 2013. p. e68827. [23] Tejasvi T, Stuart PE, Chandran V, Voorhees JJ, Gladman DD, Rahman P, et al. TNFAIP3 gene polymorphisms are associated with response to TNF blockade in psoriasis. J Invest Dermatol 2012;132(3 Pt 1):593–600. http://dx.doi.org/ 10.1038/jid.2011.376. [24] Sa SM, Valdez PA, Wu J, Jung K, Zhong F, Hall L, et al. The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J Immunol 2007;178(4):2229–40. [25] Tohyama M, Hanakawa Y, Shirakata Y, Dai X, Yang L, Hirakawa S, et al. IL-17 and IL-22 mediate IL-20 subfamily cytokine production in cultured keratinocytes via increased IL-22 receptor expression. Eur J Immunol 2009;39(10):2779–88. http://dx.doi.org/10.1002/eji.200939473.

Please cite this article in press as: Grine L, et al. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.10.009

G Model

CGFR-841; No. of Pages 9 8

L. Grine et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

[26] Kunz S, Wolk K, Witte E, Witte K, Doecke W-D, Volk H-D, et al. Interleukin (IL)19, IL-20 and IL-24 are produced by and act on keratinocytes and are distinct from classical ILs. Exp Dermatol 2006;15(12):991–1004. http://dx.doi.org/ 10.1111/j.1600-0625.2006.00516.x. [27] Kumari S, Bonnet MC, Ulvmar MH, Wolk K, Karagianni N, Witte E, et al. Tumor necrosis factor receptor signaling in keratinocytes triggers interleukin-24-dependent psoriasis-like skin inflammation in mice. Immunity 2013;39(5):899–911. http://dx.doi.org/10.1016/j.immuni.2013.10.009. [28] Rømer J, Hasselager E, Nørby PL, Steiniche T, Thorn Clausen J, Kragballe K. Epidermal overexpression of interleukin-19 and -20 mRNA in psoriatic skin disappears after short-term treatment with cyclosporine a or calcipotriol. J Invest Dermatol 2003;121(6):1306–11. http://dx.doi.org/10.1111/j.15231747.2003.12626.x. [29] He M, Liang P. IL-24 transgenic mice: in vivo evidence of overlapping functions for IL-20, IL-22, and IL-24 in the epidermis. J Immunol 2010;184(4):1793–8. http://dx.doi.org/10.4049/jimmunol.0901829. [30] Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci 1957;147(927):258–67. [31] Jaeckel E, Cornberg M, Wedemeyer H, Santantonio T, Mayer J, Zankel M. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med 2001;345(20):1452–7. http://dx.doi.org/10.1056/NEJMoa011232. [32] Perrillo R. Benefits and risks of interferon therapy for hepatitis B. Hepatology 2009;49(5 (Suppl)):S103–11. http://dx.doi.org/10.1002/he22956. [33] La Mantia L, Capsoni F. Psoriasis during interferon beta treatment for multiple sclerosis. Neurol Sci 2010;31(3):337–9. http://dx.doi.org/10.1007/s10072009-0184-x. [34] Afshar M, Martinez a D, Gallo RL, Hata TR. Induction and exacerbation of psoriasis with Interferon-alpha therapy for hepatitis C: a review and analysis of 36 cases. J Eur Acad Dermatol Venereol 2013;27(6):771–8. http://dx.doi.org/ 10.1111/j.1468-3083.2012.04582.x. [35] Nestle FO, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boyman O, et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med 2005;202(1):135–43. http://dx.doi.org/10.1084/ jem.20050500. [36] Tsoi LC, Spain SL, Knight J, Ellinghaus E, Stuart PE, Capon F, et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet 2012;44(12):1341–8. http://dx.doi.org/10.1038/ng.2467. [37] Bijlmakers M-J, Kanneganti SK, Barker JN, Trembath RC, Capon F. Functional analysis of the RNF114 psoriasis susceptibility gene implicates innate immune responses to double-stranded RNA in disease pathogenesis. Hum Mol Genet 2011;20(16):3129–37. http://dx.doi.org/10.1093/hmg/ddr215. [38] Hida S, Ogasawara K, Sato K, Abe M, Takayanagi H, Yokochi T, et al. CD8(+) T cell-mediated skin disease in mice lacking IRF-2, the transcriptional attenuator of interferon-alpha/beta signaling. Immunity 2000;13(5):643–55. [39] van der Fits L, Mourits S, Voerman JSA, Kant M, Boon L, Laman JD, et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol 2009;182(9):5836–45. http://dx.doi.org/ 10.4049/jimmunol.0802999. [40] Walter A, Scha¨fer M, Cecconi V, Matter C, Urosevic-Maiwald M, Belloni B, et al. Aldara activates TLR7-independent immune defence. Nat Commun 2013;4:1560. http://dx.doi.org/10.1038/ncomms2566. [41] Wohn C, Ober-Blo¨baum JL, Haak S, Pantelyushin S, Cheong C, Zahner SP, et al. Langerin(neg) conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice. Proc Natl Acad Sci U S A 2013;110(26):10723–28. http://dx.doi.org/10.1073/pnas.1307569110. [42] Ueyama A, Yamamoto M, Tsujii K, et al. Mechanism of pathogenesis of imiquimod-induced skin inflammation in the mouse: a role for interferonalpha in dendritic cell activation by imiquimod. J Dermatol 2014;41(2):135– 43. http://dx.doi.org/10.1111/1346-8138.12367. [43] Bissonnette R, Papp K, Maari C, Yao Y, Robbie G, White WI, et al. A randomized, double-blind, placebo-controlled, phase I study of MEDI545, an anti-interferon-alfa monoclonal antibody, in subjects with chronic psoriasis. J Am Acad Dermatol 2010;62(3):427–36. http://dx.doi.org/ 10.1016/j.jaad.2009.05.042. [44] Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005;201(2):233–40. http://dx.doi.org/10.1084/ jem.20041257. [45] Qu N, Xu M, Mizoguchi I, Furusawa J, Kaneko K, Watanabe K, et al. Pivotal roles of T-helper 17-related cytokines, IL-17, IL-22, and IL-23, in inflammatory disease. Clin Dev Immunol 2013;2013. http://dx.doi.org/10.1155/2013/ 968549. Article ID 968549. [46] Fitch E, Harper E, Skorcheva I, Kurtz SE, Blauvelt A. Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep 2007;9(6):461–7. [47] Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med 2004;199(1):125–30. http://dx.doi.org/ 10.1084/jem.20030451. [48] Pantelyushin S, Haak S, Ingold B, Kulig P, Heppner FL, Navarini AA, et al. Rorgt+ innate lymphocytes and gd T cells initiate psoriasiform plaque formation in mice. J Clin Invest 2012;122(6):2252–6. http://dx.doi.org/10.1172/JCI61862. [49] Guo X, Jiang X, Xiao Y, Zhou T, Guo Y, Wang R, et al. IL-17A signaling in colonic epithelial cells inhibits pro-inflammatory cytokine production by enhancing the activity of ERK and PI3K, Mizoguchi E, ed.. PLOS ONE 2014;9(2):e89714. http://dx.doi.org/10.1371/journal.pone.0089714.

[50] Wedebye Schmidt EG, Larsen HL, Kristensen NN, Poulsen SS, Lynge Pedersen AM, Claesson MH, et al. TH17 cell induction and effects of IL-17A and IL-17F blockade in experimental colitis. Inflamm Bowel Dis 2013;19(8):1567–76. http://dx.doi.org/10.1097/MIB.0b013e318286fa1c. [51] McLean LP, Cross RK, Shea-Donohue T. Combined blockade of IL-17A and IL17F may prevent the development of experimental colitis. Immunotherapy 2013;5(9):923–5. http://dx.doi.org/10.2217/imt.13.87. [52] Tse MT. IL-17 Antibodies Gain Momentum. Nature Publishing Group; 2014. p. 815–6. http://dx.doi.org/10.1038/nrd 4152. [53] Yarilina A, Ivashkiv LB. Type I interferon: a new player in TNF signaling. Curr Dir Autoimmun 2010;11:94–104. http://dx.doi.org/10.1159/900028919. [54] Rosengren S, Corr M, Firestein GS, Boyle DL. The JAK inhibitor CP-690,550 (tofacitinib) inhibits TNF-induced chemokine expression in fibroblast-like synoviocytes: autocrine role of type I interferon. Ann Rheum Dis 2012;71(3):440–7. http://dx.doi.org/10.1136/ard.2011.841502. [55] Huys L, Van Hauwermeiren F, Dejager L, Dejonckheere E, Lienenklaus S, Weiss S, et al. Type I. interferon drives tumor necrosis factor-induced lethal shock. J Exp Med 2009;206(9):1873–82. http://dx.doi.org/10.1084/jem.20090213. [56] Angelot F, Seille`s E, Biichle´ S, Berda Y, Gaugler B, Plumas J, et al. Endothelial cell-derived microparticles induce plasmacytoid dendritic cell maturation: potential implications in inflammatory diseases. Haematologica 2009;94(11):1502–12. http://dx.doi.org/10.3324/haematol.2009.340109. [57] Palucka AK, Blanck J-P, Bennett L, Pascual V, Banchereau J. Cross-regulation of T.N.F. IFN-alpha in autoimmune diseases. Proc Natl Acad Sci USA 2005;102(9):3372–7. http://dx.doi.org/10.1073/pnas.0408506102. [58] Ju X, Zenke M, Hart DNJ, Clark GJ. CD300a/c regulate type I interferon and TNFalpha secretion by human plasmacytoid dendritic cells stimulated with TLR7 and TLR9 ligands. Blood 2008;112(4):1184–94. http://dx.doi.org/10.1182/ blood-2007-12-511279. [59] Dutz JP. Tumor necrosis factor-a inhibition and palmoplantar pustulosis: Janus-faced therapy? J Rheumatol 2007;34(2):247–9. [60] Alekseyenko AV, Perez-Perez GI, De Souza A, Strober B, Gao Z, Bihan M, et al. Community differentiation of the cutaneous microbiota in psoriasis. Microbiome 2013;1(1):31. http://dx.doi.org/10.1186/2049-1-312618. [61] Trivedi B, Microbiome:. The surface brigade. Nature 2012;492(7429):S60–1. http://dx.doi.org/10.10/492S60a1038. [62] Castelino M, Eyre S, Upton M, Ho P, Barton A. The bacterial skin microbiome in psoriatic arthritis, an unexplored link in pathogenesis: challenges and opportunities offered by recent technological advances. Rheumatology 2014;53(5):777–84. http://dx.doi.org/10.1093/rheumatology/ket319. [63] Mavragani CP, La DT, Stohl W, Crow MK. Association of the response to tumor necrosis factor antagonists with plasma type I interferon activity and interferon-beta/alpha ratios in rheumatoid arthritis patients: a post hoc analysis of a predominantly Hispanic cohort. Arthritis Rheum 2010;62(2):392–401. http://dx.doi.org/10.1002/art.62722. [64] Raterman HG, Vosslamber S, de Ridder S, Nurmohamed MT, Lems WF, Boers M, et al. The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients. Arthritis Res Ther 2012;14(2):R95. http://dx.doi.org/10.1186/ar3819. [65] Keeley K, Bell J. The immunological basis for treatment resistance to anti-TNF treatments. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US); 2014. 2000-[cited 2014 August 28] Available from: http:// clinicaltrials.gov/show/NCT01971346NLM identifier: NCT01971346. [66] Giacomoni PU, editor. Biophysical and physiological effects of solar radiation on human skin. Cambridge: Royal Society of Chemistry; 2007 . http://dx.doi.org/10.1039/9781847557957. [67] Haig DM, Hutchison G, Green I, Sargan D, Reid HW. The effect of intradermal injection of GM-CSF and TNF-a on the accumulation of dendritic cells in ovine skin. Vet Dermatol 2008;6(4):211–20. http://dx.doi.org/10.1111/j.13653164.1995.tb00067.x. [68] Antonopoulos C, Cumberbatch M, Dearman RJ, Daniel RJ, Kimber I, Groves RW. Functional caspase-1 is required for langerhans cell migration and optimal contact sensitization in mice. American Association of Immunologists; 2001. p. 3672–7. http://dx.doi.org/10.4049/jimmunol.166.6. [69] Cho K-A, Suh JW, Lee KH, Kang JL, Woo SY. IL-17 and IL-22 enhance skin inflammation by stimulating the secretion of IL-1b by keratinocytes via the ROS-NLRP3-caspase-1 pathway. Int Immunol 2012;24(3):147–58. http:// dx.doi.org/10./intimm/dxr1101093. [70] Maione F, Paschalidis N, Mascolo N, Dufton N, Perretti M, D’Acquisto F. Interleukin 17 sustains rather than induces inflammation. Biochem Pharmacol 2009;77(5):878–87. http://dx.doi.org/10.1016/j.bcp.11.0112008. [71] Albanesi C, Scarponi C, Cavani A, Federici M, Nasorri F, Girolomoni G. Interleukin-17 is produced by both Th1 and Th2 lymphocytes, and modulates interferon-gamma- and interleukin-4-induced activation of human keratinocytes. J Invest Dermatol 2000;115(1):81–7. http://dx.doi.org/10.1046/j.15231747.2000.1.x0004. [72] Griffin GK, Newton G, Tarrio ML, Bu D, Maganto-Garcia E, Azcutia V, et al. IL-17 and TNF-a sustain neutrophil recruitment during inflammation through synergistic effects on endothelial activation. J Immunol 2012;188(12):6287–99. http://dx.doi.org/10.4049/jimmunol.1200385. [73] Wang CQF, Akalu YT, Suarez-Farinas M, Gonzalez J, Mitsui H, Lowes MA, et al. IL-17 and TNF synergistically modulate cytokine expression while suppressing melanogenesis: potential relevance to psoriasis. J Invest Dermatol 2013;133(12):2741–52. http://dx.doi.org/10.1038/jid.2013237. [74] Ruddy MJ, Shen F, Smith JB, Sharma A, Gaffen SL. Interleukin-17 regulates expression of the CXC chemokine LIX/CXCL5 in osteoblasts: implications for

Please cite this article in press as: Grine L, et al. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.10.009

G Model

CGFR-841; No. of Pages 9 L. Grine et al. / Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx

[75]

[76]

[77]

[78]

[79]

[80] [81]

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

inflammation and neutrophil recruitment. J Leukoc Biol 2004;76(1):135–44. http://dx.doi.org/10.1189/jlb.0204065. Nonaka M, Ogihara N, Fukumoto A, Sakanushi A, Kusama K, Pawankar R, et al. Synergistic induction of macrophage inflammatory protein-3a;/CCL20 production by interleukin-17A and tumor necrosis factor-A; in nasal polyp fibroblasts. World Allergy Organ J 2009;2(10):218–23. http://dx.doi.org/ 10.1097/WOX.0b013e3181bdd219. Iyoda M, Shibata T, Kawaguchi M, Hizawa N, Yamaoka T, Kokubu F, et al. IL-17A and IL-17F stimulate chemokines via MAPK pathways (ERK1/2 and p38 but not JNK) in mouse cultured mesangial cells: synergy with TNF-alpha and IL-1beta. Am J Physiol Renal Physiol 2010;298(3):F779–87. http://dx.doi.org/10.1152/ ajprenal.00198.2009. Koenders MI, Marijnissen RJ, Devesa I, Lubberts E, Joosten LA, Roth J, et al. Tumor necrosis factor-interleukin-17 interplay induces S100A8, interleukin1b, and Matrix metalloproteinases, and drives irreversible cartilage destruction in murine arthritis: rationale for combination treatment during arthritis. Arthritis Rheum 2011;63(8):2329–39. http://dx.doi.org/10.1002/art.30418. Mose M, Kang Z, Raaby L, Iversen L, Johansen C. TNFa- and IL-17A-mediated S100A8 expression is regulated by p38 MAPK. Exp Dermatol 2013;22(7):476– 81. http://dx.doi.org/10.1111/exd.12187. Donetti E, Cornaghi L, Gualerzi A, Baruffaldi Preis FW, Prignano F. An innovative three-dimensional model of normal human skin to study the proinflammatory psoriatic effects of tumor necrosis factor-alpha and interleukin-17. Cytokine 2014;68(1):1–8. http://dx.doi.org/10.1016/j.cyto.2014.03.003. Covagen. Covagen initiates phase Ib/IIa study of bispecific anti-TNF/IL-17A FynomAb COVA322. Reuters May 2014. Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, et al. Genemicroarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 2002;8(5):500–8. http:// dx.doi.org/10.1038/nm0502-500. Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 2008;172(1):146–55. http://dx.doi.org/10.2353/ajpath.2008.070690. Brucklacher-Waldert V, Stuerner K, Kolster M, Wolthausen J, Tolosa E. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain 2009;132(Pt 12):3329–41. http://dx.doi.org/10.1093/brain/ awp289. Kostic M, Dzopalic T, Zivanovic S, Zivkovic N, Cvetanovic A, Stojanovic I, et al. IL-17 and glutamate excitotoxicity in the pathogenesis of multiple sclerosis. Scand J Immunol 2014;79(3):181–6. http://dx.doi.org/10.1111/sji.12147. Matusevicius D, Kivisa¨kk P, He B, Kostulas N, Ozenci V, Fredrikson S, et al. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler 1999;5(2):101–4. Murugaiyan G, Mittal A, Lopez-Diego R, Maier LM, Anderson DE, Weiner HL. IL27 is a key regulator of IL-10 and IL-17 production by human CD4+ T cells. J Immunol 2009;183(4):2435–43. http://dx.doi.org/10.4049/jimmunol.0900568. Gu Y, Yang J, Ouyang X, Liu W, Li H, Yang J, et al. Interleukin 10 suppresses Th17 cytokines secreted by macrophages and T cells. Eur J Immunol 2008;38(7):1807–13. http://dx.doi.org/10.1002/eji.200838331. Zhang X, Markovic-Plese S. Interferon beta inhibits the Th17 cell-mediated autoimmune response in patients with relapsing-remitting multiple sclerosis. Clin Neurol Neurosurg 2010;112(7):641–5. http://dx.doi.org/10.1016/j.clineuro.2010.04.020. Alexander JS, Harris MK, Wells SR, Mills G, Chalamidas K, Ganta VC, et al. Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-beta1b. Mult Scler 2010;801–9. http:// dx.doi.org/10.1177/1352458510370791. Axtell RC, de Jong BA, Boniface K, van der Voort LF, Bhat R, De Sarno P, et al. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med 2010;16(4):406–12. http://dx.doi.org/10.1038/nm.2110. Ba˘las¸a R, Bajko Z, Hut¸anu A. Serum levels of IL-17A in patients with relapsingremitting multiple sclerosis treated with interferon-b. Mult Scler 2013;19(7):885–90. http://dx.doi.org/10.1177/1352458512468497. Ra´cz E, Prens EP, Kurek D, Kant M, de Ridder D, Mourits S, et al. Effective treatment of psoriasis with narrow-band UVB phototherapy is linked to suppression of the IFN and Th17 pathways. J Invest Dermatol 2011;131(7):1547–58. http://dx.doi.org/10.1038/jid.2011.53. Gregorio J, Meller S, Conrad C, Di Nardo A, Homey B, Lauerma A, et al. Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons. J Exp Med 2010;207(13):2921–30. http:// dx.doi.org/10.1084/jem.20101102.

9

[94] Tohyama M, Yang L, Hanakawa Y, Dai X, Shirakata Y, Sayama K. IFN-A enhances IL-22 receptor expression in keratinocytes: a possible role in the development of psoriasis. J Invest Dermatol 2012;1933–5. http://dx.doi.org/10.1038/ jid.2011.468. [95] Guilloteau K, Paris I, Pedretti N, Boniface K, Juchaux F, Huguier V, et al. Skin inflammation induced by the synergistic action of IL-17A, IL-22, oncostatin M, IL-1{alpha}, and TNF-{alpha} recapitulates some features of psoriasis. J Immunol 2010. http://dx.doi.org/10.4049/jimmunol.0902464. [96] Van der Fits L, van der Wel LI, Laman JD, Prens EP, Verschuren MCM. In psoriasis lesional skin the type I interferon signaling pathway is activated, whereas interferon-alpha sensitivity is unaltered. J Invest Dermatol 2004;122(1):51–60. http://dx.doi.org/10.1046/j.0022-202X.2003.22113.x. [97] Christophers E, Metzler G, Ro¨cken M. Bimodal immune activation in psoriasis. Br J Dermatol 2014;170(1):59–65. http://dx.doi.org/10.1111/bjd.12631. [98] Mountz JD, Wang JH, Xie S, Hsu H-C. Cytokine regulation of B-cell migratory behavior favors formation of germinal centers in autoimmune disease. Discov Med 2011;11(56):76–85. [99] Gallo E, Cabaleiro T, Roma´n M, Solano-Lo´pez G, Abad-Santos F, Garcı´a-Dı´ez A, et al. The relationship between tumour necrosis factor (TNF)-a promoter and IL12B/IL-23R genes polymorphisms and the efficacy of anti-TNF-a therapy in psoriasis: a case-control study. Br J Dermatol 2013;169(4):819–29. http:// dx.doi.org/10.1111/bjd.12425.

Dr. Roosmarijn E. Vandenbroucke graduated as a Master in Biotechnology in 2001. She obtained her PhD at the Faculty of Pharmaceutical Sciences at Ghent University in 2008 on non-viral nucleic acid delivery systems. She is currently postdoctoral scientist (FWO Vlaanderen) in the group of Prof. Dr. Claude Libert at the VIB, Belgium. Her research focusses on the role of MMPs, TNFR1 and IFNAR1 in inflammation and aging.

Prof. Dr. Claude Libert obtained his PhD in Molecular Biology in 1993 in the lab of Walter Fiers. After a postdoc in the IRBM in Rome, Italy, he became a group leader with VIB in 1997 and a professor at Ghent University in 2003. His main interest is the elucidation of molecular mechanism of complex inflammatory reactions and the identification of new players. His approach is a mouse molecular genetic approach and his aim is to define novel therapeutic interventions. Currently, his group consists of 18 researchers.

Dr. Lien Dejager finished her PhD in Biotechnology from the University of Ghent in 2010 under the promotership of Prof. Claude Libert, IRC, VIB. Afterwards she became a postdoctoral researcher at FWO-Vlaanderen in the same group. Her major research interests are elucidating the anti-inflammatory mechanisms of glucocorticoids and the mechanisms underlying glucocorticoid resistance, aiming to design more efficient glucocorticoid-based therapies.

Dr. Lynda Grine obtained her master’s degree in Biochemistry & Biotechnology and her PhD in Biotechnology at Ghent University, Belgium. Her work is focused on the interaction of type I Interferons in TNF-mediated inflammation.

Please cite this article in press as: Grine L, et al. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.10.009