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

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Abstract

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 IL-23/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.

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 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 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], [3], [4], [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], [7], [8], [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], [11], [12], [13], [14]. These antibodies are already in clinical trials or on the market, though their long-term 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.

Section snippets

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

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 IFNα and IFNβ, 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 IL-23/IL-17 axis by neutralizing IL-17A, IL-17F,

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.

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.

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    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.

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    Both authors contributed equally.

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