Update on the role of Interleukin 17 in rheumatologic autoimmune diseases

Cytokine xxx (2015) xxx–xxx

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Update on the role of Interleukin 17 in rheumatologic autoimmune diseases Christine Konya 1, Ziv Paz ⇑,1, Sokratis A. Apostolidis, George C. Tsokos Rheumatology Department at Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, United States

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Article history: Received 17 September 2014 Received in revised form 2 January 2015 Accepted 9 January 2015 Available online xxxx Keywords: Interleukin-17 Autoimmune diseases Biological agents

a b s t r a c t Interleukin 17 is a proinflammatory cytokine produced by CD4+ T cells when in the presence of a distinct set of cytokines and other cells. Preclinical and clinical studies have assigned a role to IL-17 in tissue inflammation and damage in patients with rheumatoid arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis and systemic lupus erythematosus. Antibodies blocking the action of IL-17 have already been approved to treat patients with psoriasis and it is expected that they may also benefit patients with other rheumatic diseases. Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction Recently, anti-interleukin 17 A (IL-17A) monoclonal antibodies were approved by the FDA for treatment of psoriatic arthritis [1–3]. This achievement is the result of almost two decades of extensive translational work. The scope of this review is to summarize this work and present our current understanding of the role of IL-17 in health and in disease. Interleukin 17A (IL-17A), mostly referred to as IL-17, was discovered in 1993 and consists of 155-amino acids [4,5]. Homology-based cloning has revealed five additional homologous cytokines, named IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. The most studied members of this family are IL-17A and IL-17F [6]. IL-17F shares the highest homology (60%) with IL-17A. The genes encoding for IL-17A and IL-17F are closely clustered on chromosome 1A4 in mouse and 6p12 in humans. IL-17A and IL-17F can be secreted as homodimers as well as heterodimers. The IL-17A/F heterodimer is more potent than the IL-17F homodimer but less potent than the IL-17A homodimer in inducing inflammatory response [7–9]. In the early 2000s the cytokine IL-17A was shown to drive joint destruction in rheumatoid arthritis mouse models [10–12]. Previously, it was shown that IL-23 stimulation of CD4+ T cells leads to IL-17A production [5,13]. However, it was not until 2005 ⇑ Corresponding author. Tel.: +1 617 735 4160. E-mail addresses: [email protected] (C. Konya), [email protected]. edu (Z. Paz), [email protected] (S.A. Apostolidis), gtsokos@bidmc. harvard.edu (G.C. Tsokos). 1 The first two authors equally contributed to this publication.

when Th17 cells (e.g. T helper cells that produce IL-17) were defined as a separate sub-population distinct from Th1 and Th2 cells and pro-inflammatory in nature [14,15]. Since that discovery and over the last decade the Th17 cell became its own field of research interest. In addition to Th17 cells, other subsets of T cells such as cd-T and natural killer T (NKT) cells have also been found to produce IL-17 in response to different stimuli [16–19]. The IL-17 receptors represent a distinct family of type I transmembrane receptors, which includes IL-17RA, IL-17RB, IL-17RC, IL-17RD and IL-17RE [20,21]. IL-17RA (or IL-17R) was the first described IL-17 receptor, and initially identified as the receptor for human IL-17A and for Herpesvirus Saimiri [22]. Later it was shown that IL-17RA also binds IL-17F [23]. It appears to be ubiquitously expressed on multiple cell types including epithelial cells, fibroblasts, endothelial cells and osteoblasts, with the highest expression on hematopoietic cells [24,25]. IL-17RA subunits are preassembled on the cell membrane before ligand binding, which enables a rapid response once they bind their ligand [26,27]. After IL-17A binds to the receptor, IL-17RA surface expression decreases fast by internalization of the cytokine as a self-limiting mechanism [28].

2. Regulatory mechanisms of IL-17 production Naïve CD4+ T cells differentiate into different cell linages when stimulated with various cytokines (Fig. 1) [29,30]. Th1 differentiation is facilitated by the cytokines IL-12 and IFNc through activation of the Stat1 and Stat 4 pathways. The key transcription factor for Th1 programing is Tbet. The Th1 response is classically

http://dx.doi.org/10.1016/j.cyto.2015.01.003 1043-4666/Ó 2015 Elsevier Ltd. All rights reserved.

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Fig. 1. Distinct T cell linages and Th17 differentiation. Naïve CD4+ T cells differentiate into different cell linages when stimulated in the presence of various cytokines. Th1 differentiation requires IL-12 and IFNc and the key transcription factor for Th1 programing Tbet. Th2 differentiation requires IL-4 and the key transcription factor for Th2 programing Gata3. Treg cell differentiation requires IL-2 and TGFb and the key transcription factor Foxp3. Th17 differentiation is induced by IL-1b and co-stimulation with IL6 and TGFb. Th17 differentiation is amplified and maintained by IL-23. IL-17 production is mainly controlled by the transcription factor ROR c and its immune cell-specific isoform RORct. IL-17 secreted by Th17 cells binds the IL-17R receptor on the effector cell to induce an inflammatory response. IFNc: Interferon c; Tbet: T-box transcription factor; IL: Interleukin; Treg: T regulatory cells; TGFb: transforming growth factor beta; RORc: retinoic acid-related orphan receptor c.

characterized by IFNc production. Th2 differentiation is induced in the presence of IL-4 through activation of the Stat6 pathway. The key transcription factor for Th2 programing is Gata3. Th2 cells secrete IL-4, IL-5 and IL-13. Even though there was earlier evidence for T cells with suppressive function, it was not until 1995 when Sakaguchi and colleagues described the T regulatory cell (Tregs) and identified the CD25 receptor as its marker [31]. Treg cells are able to prevent autoimmunity by controlling the response of the immune system to auto-antigens. The key transcription factor of the Treg cell linage is Foxp3 [32]. On the other hand, IL-17 production is mainly controlled by the ubiquitously expressed transcription factor retinoic acid-related orphan receptor (ROR) c and its immune cell-specific isoform RORct [33,34]. RORct is encoded by the genetic locus (Rorc) and belongs to a large family of hormone nuclear receptors [35,36]. For complete Th17 differentiation, RORct needs to cooperate with other transcription factors, including STAT3, interferon regulatory factor 4 (IRF4) and runt-related transcription factor 1 (Runx1) [37–40]. Both, Th17 and Treg differentiation seems to require the presence of TGFb. TGFb stimulation of CD4+ T cells induces Treg differentiation and induction of the transcription factor Foxp3 [41]. Interestingly, TGFb and IL-6 co-stimulation forces the CD4+ T cell to differentiate into a Th17 cell and to express the transcription factor RORct [42–44]. It was shown that naïve murine T cells which lack the IL-23R do not differentiate into Th17 cells. However, when these CD4+ T cells are co-stimulated with anti-CD3 and CD28 and cultured with IL-6 and TGFb, they do differentiate into Th17 cells. These studies showed that IL-23 is not necessary for the induction of Th17 cells but is needed mainly for their amplification and maintenance [45–47]. Another cytokine that is important to the expression of RORct and Th17 differentiation is IL-21. New studies demonstrated that interferon regulatory

factors (IRFs) are required for the T cells response to IL-21. More specifically, IRF4 is involved in the IL-21 mediated downregulation of Foxp3 and is important in balancing Foxp3 and RORct expression and therefore balancing between Treg and Th17 differentiation [39,48–51]. Other factors which are essential for Th17 differentiation are STAT3 and STAT5. STAT3 regulates multiple genes which contribute to the function and regulation of Th17. For example, STAT3 binds to the IL17 locus and to the Rorc gene and modulates its transcription [52,53]. The inhibitory effects of STAT5 were realized overtime. Early observations showed that when Treg cells are incubated with naïve CD4 T cells, Th17 differentiation increases [43]. The current explanation is that Treg cells act as IL-2 ‘sinks’. By consuming IL-2, a known inhibitor of Th17 differentiation, they promote the differentiation of Th17 cells [54]. The inhibitory effects of IL-2 on Th17 differentiation was shown to be mediated by STAT5, which competes with STAT3 binding sites [52]. We now know that the balance between STAT3 and STAT5 determines the fate of the T cells (Fig. 2). It seems that human Th17 cells are different when compared to their mouse counterparts. Human Th17 cells produce IFN-c and it is hard to find pure population of human IL17+ IFN-c T cells, which on the other hand are easily generated in mice [55]. We just start to understand the importance of epigenetics in the regulation of IL-17 production and the differentiation of Th17. Studies so far focused on the epigenetic effects at the IL-17 promoter. Similar to the differentiation of Th1 and Th2 cell lineages, differentiation of Th17 cells is associated with selective chromatin remodeling. For example, Lys-4 tri-methylation is specifically associated with the promoters of the IL-17A and IL-17F genes in the Th17 lineage. Furthermore, there are multiple noncoding sequences within the loci of the IL-17A and IL-17F genes that are

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Fig. 2. The balance between STAT3 and STAT5 regulates Th17 differentiation and IL-17 production. The transcription factor STAT3 is induced by co-stimulation of Th17 cells with IL-6 and TGFb. STAT3 binds to the IL17 locus and increases the IL-17 promoter activity. The transcription factor STAT5 represses Th17 differentiation and IL-17 production. IL-2 leads to increase in the levels of STAT5 in Th17 cells. The balance between STAT3 and STAT5 determines the fate of the T cells. STAT: Signal transducer and activator of transcription; IL: Interleukin; TGFb: transforming growth factor beta.

conserved across species and are associated with hyperacetylation of histone 3 in a Th17-specific manner [56–59]. These are only two examples for the strong association between specific modifications to Th17 differentiation. However, the mechanisms in which these epigenetic modifications are induced or lead to Th17 differentiation are still obscure. 3. Other cellular sources of IL-17 production Although Th17 cells are named after their ability to produce IL-17 and represent a main source of IL-17 production, other cells can secrete IL-17. cd T cells are an important source of IL-17 and during infections with Escherichia coli, Mycobacterium tuberculosis and Klebsiella pneumonia produce large amounts of IL-17 and help combat disease [16,60,61]. Mice which lack cd T cells produce less IL-17 and have a higher susceptibility to staphylococcus aureus infections, as these cells are an important source of IL-17 and important to combat skin infections [62,63]. Neutrophils, when stimulated with IL-15, are also able to secrete IL17 [64]. Studies have shown that certain memory CD8+ T, after stimulation with PMA and ionomycin, can produce IL-17 [65]. This observation was supported by the fact that also murine CD8+ T cells secrete IL-17 in response to IL-1 and IL-23 [66]. Finally, stimulated NKT IL-23R+ cells, which were cultured with IL-23 and anti-CD3, also produce IL-17 [18]. Taken together, it seems that IL-17 is not produce solely by a specific set of T cells but a more generic cytokine that produce by different inflammatory cells in the context of milieu of pro-inflammatory cytokines and in turn lead to propagation of the inflammatory response.

4. IL-17 receptors and mechanism of signaling The IL-17 receptor family includes five receptor subunits, IL-17RA to IL-17RE (Fig. 3). The IL-17 receptors are single trans-membrane proteins encoded by chromosome 3 in humans. Among the IL-17R subunits, IL-17RA is the most commonly expressed. IL-17RA forms together with IL17RC the binding site for IL-17A and IL-17F. IL-17RB and IL-17RA form a heterodimer receptor, which binds IL-17E. IL-17RB homodimer are binding IL-17B and IL17RE homodimer binds IL-17C. The receptor for IL-17D is so far unknown as is the ligand for IL-17RD [20,67]. IL-17RA is highly expressed on the surface of different hematopoietic cells, including macrophages and neutrophils [24]. It is also found on other cells including epithelial cells and fibroblasts. Studies suggest that once IL-17 binds to the IL-17RA receptor, it initiates a signaling cascade that leads to a pro-inflammatory response, similar to the ones initiated by TLR receptors. IL-17RA, in difference from other interleukin receptors, which signal through Jak/Stat pathway, it activates the adaptor protein1 (ACT1) via its intracellular/cytoplasmic domain called SEFIR (SEF/IL-17R) [67–69]. Activated ACT1 activates the pro-inflammatory NFkB pathway together with TNF receptor associated factor 6 (TRAF6). In addition, ACT1 activates the mitogen-activated protein kinase (MAPK) pathway, which leads to activation of the transcription factor-activator protein 1 (AP-1) [69,70]. 5. The role of IL17 in the pathogenesis of autoimmune diseases The major role of IL-17A and IL-17F is in the defense against infectious processes. Its secretion is important in fighting multiple

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Fig. 3. Interleukin 17 binds IL-17 receptor on effector cells. Interleukin 17 A and F are secreted as homodimers or IL-17 A/F heterodimers. The IL-17 receptor which binds IL17A and IL-17F is composed of the two subunits: IL-17RA and IL17RC. IL-17RA signals through ACT1, which activates TRAF6 and the NFkB pathway. Activation of TRAF6 leads to activation of the MAP Kinases and the transcription factor AP-1. AP-1 and the NFkB pathway are involved in the transcription of different pro-inflammatory cytokines. ACT1: Adaptor protein 1; TRAF6: TNF receptor associated factor 6; MAPK: mitogen-activated protein kinase; AP-1: activator-protein 1; NFkB: nuclear factor kappa-lightchain-enhancer of activated B cells; IL: Interleukin.

pathogens including Mycobacteria, Listeria, Klebsiella and Staphylococcus as well as in fungi, as mentioned above. However, excessive and uncontrolled production can lead to chronic inflammation and autoimmune disease. Excessive or persistent secretion of IL-17 from activated cells leads to excretion of IL-6 and matrix metalloproteinase (MMP) from fibroblasts and endothelial cells as well as to increase in the TNF production by the dendritic cells (DC) [10,71,72]. IL-6 by itself leads to increased production of the inflammatory marker C-reactive protein in the liver. IL-17 is also associated with RANK ligand activation and leads to osteoclastogenesis and bone absorption. RANK ligand activation in turn activates the NFkB pathway and leads to increased IL-6 production, bone remodeling, and cartilage destruction through MMP and nitric oxide (NO) [73–76].

5.1. Rheumatoid arthritis (RA) Rheumatoid arthritis is a chronic systemic autoimmune disease, which affects the joints. It causes inflammation of the synovium, and overtime leads to joint destruction. Even before the identification of Th17 as a separate population, a significant percentage of the T cells isolated from RA patients were found to produce IL-17 [14]. The role of Th17 in RA pathophysiology is supported by the fact that the inflamed synovium in RA has an abundant amount of Th17 especially when compared to synovium obtained from patients with osteoarthritis [10]. In addition, the levels of IL-17 in the synovial tissue correlate with the disease activity and severity [77]. To demonstrate the importance of IL-17 in RA an arthritis prone mouse models (collagen type II immunized mice) were

manipulated and assessed. IL-17 overexpression in the knee joints of these mice led to chronic inflammation and joint destruction. Whereas IL-17-deficient collagen type II immunized mice develops significantly less arthritis. In addition, antibody-mediated inhibition of IL-17 diminished inflammation and slowed disease progression [11,12,78]. The way IL-17 mediates its effects and contributes to the pathophysiology of in RA is complex and not completely understood. However, few observations were made over the years. IL-17 induces the release of proinflammatory cytokines from fibroblasts, osteoblasts, chondrocytes, macrophages and the synovium. It also induces the production of NO and prostaglandin E2 which contribute further to the production of inflammatory cytokines [79–81]. In addition, IL-17 was demonstrated to activate the complement system and the innate arm of the immune system including TLRs, which showed to be associated with inflammation in RA [82–84]. Moreover, IL-17 down regulates miR-23b, a micro-RNA, which is associated with IL-17 regulation and suppression [85]. IL-17 was also shown to upregulate the anti-apoptotic molecule Bcl-2 (B-cell lymphoma 2) in synoviocytes and block apoptosis [86].

5.2. Systemic lupus erythematosus (SLE) Systemic lupus erythematosus is a systemic autoimmune disease involving multiple organs. It can manifest itself in many ways and it has an unpredictable disease course. Many cellular and molecular pathways have been found to be involved in the pathophysiology of SLE, including the IL-17 pathway. SLE patients have elevated serum levels of IL-17. The increase in IL-17 correlates with

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the disease severity and activity, which implies that Th17 mediated inflammation, plays a key role in this disease [87]. Over the last few years our lab demonstrated that the IL-23/IL-17 axis plays a major role in lupus nephritis. To investigate the role of IL-23/IL-17 axis in SLE we used different mice models. We first showed that IL-23 receptor deficient lupus-prone mice did not develop lupus nephritis. We then isolated lymph node cells from lupus prone mice, treated them with IL-23 and transferred them into a non-autoimmune, lymphocyte-deficient Rag-1(-/-) mice, which developed signs of nephritis [88,89]. We were also able to demonstrate that double negative T cells (TCR-ab + CD4-CD8-) as well as Th17 cells are found in renal biopsies of patients with lupus nephritis, suggesting that IL-17 contributes to the inflammatory response in lupus nephritis both in human and in mice [90]. 5.3. Psoriasis and spondyloarthropathies Psoriasis is part of a group of conditions called spondyloarthropathies. These conditions share the same genetic predisposition (e.g. HLAB27) and overlap in the clinical manifestations. Over the last few decades there was a shift in the way we understand the pathophysiology of psoriasis. We now know that psoriasis is a systemic T cell mediated autoimmune disease and not a limited skin disease. Skin biopsies taken from psoriatic plaques from patients with psoriasis revealed increased IL-17 expression and elevated levels of IL-23 and IL-6 [91–93]. Additionally, patients with psoriasis were found to have increased levels of IL-17 in the serum, which correlates with the disease activity [94,95]. Ankylosing spondylitis (AS), another form of spondyloarthropathy, is also associated with the IL-17 pathway. Bone biopsies from the sacroiliac joints of patients with AS revealed increased levels of IL-17. However studies suggest that in this case, IL-17 is not secreted by T cells but rather by local innate cells [96]. 6. Therapeutic targets As described above, IL-17 is an important pro-inflammatory cytokine and showed to be involved in the pathophysiology of

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many autoimmune conditions. As a result, there was an extensive effort over the last few years to develop targeted therapy to obviate its action. Currently, several IL-17 blocking biologics are being studied in multiple autoimmune diseases (Fig. 4). Multiple biologic agents block the IL-17 pathway directly or indirectly. Few of these agents block the cytokines required for Th17 differentiation. For example, Tocilicumab is an anti-IL-6 monoclonal antibody which was approved by the FDA for treatment of rheumatoid arthritis. Anakinra, an IL-1beta receptor antagonist used in RA, autoinflammatory disorders and recently also for gout. Other biologic agents target the IL-17 pathway directly. One of the newer biologics, which target the IL-17 axis is Ustekinumab. Ustekinumab (Centocor), trade name StelaraÒ, is a fully human monoclonal antibody, which binds the p40 subunit shared by IL-12 and IL-23. In the PHOENIX 1/2 clinical trials, patients with psoriasis treated with Ustekinumab displayed a significant reduction in the area of the psoriatic plaques and in the disease severity index compared with the placebo group and the group treated with the anti-TNF agent Etanercept [97,98]. In the PSUMMIT 1/2 trials, patients with psoriatic arthritis treated with Ustekinumab demonstrated significant and sustained improvement of disease [99,100]. Ustekinumab-treated patients also demonstrated significantly less radiographic progression compared to placebo [1]. Ustekinumab is currently approved in Canada, Europe and the United States for the treatment of moderate-to-severe plaque psoriasis. Secukinumab (Novartis) as is a fully human IgG1kappa anti-IL17A monoclonal antibody against IL-17A. Sekukinumab downregulates other pro-inflammatory cytokines including IL-12B, IL-17F, IL-22. It does have a lesser suppressive effect on IL-6 and IFN-c production. It was studied in patients with moderate to severe psoriasis and led to significant reduction in the disease severity index score (PASI) compared with the placebo group at week 4 [101–103]. In Rheumatoid arthritis trials, Secukinumab showed promising results in patients who have failed Disease-modifying antirheumatic drug (DMARD) therapy [104,105]. Ixekizumab (Eli Lilly) is a humanized IgG4 anti-IL-17A monoclonal antibody against IL-17A now being evaluated in a placebo-controlled trial in patients with moderate to severe plaque

Fig. 4. Different biological agents target the IL-17 > IL-23 axis.

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psoriasis [106]. So far early trials in rheumatoid arthritis are promising and demonstrated improved clinical signs and symptoms of disease [107].

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7. Open questions/future directions Identifying contributors which are responsible for the autoimmune response and its related pathology is challenging. The IL23 > IL17 axis contributes to inflammation and damage of the joints, the skin and the kidneys in different autoimmune conditions. However, a significant percentage of patients do not respond to treatment with IL-17 blockers. In these cases it can be stated that the IL-23 > IL-17 axis is not involved in a significant manner in the disease expression. Therefore, it is important to identify the patients in whom IL-17 is the key mediator of the organ inflammation and damage and treat them accordingly, rather than treating all the patients the same way, just because they have a similar clinical presentation and satisfy disease criteria. This consideration looms even more serious for patients with SLE in whom multiple molecular and cellular pathways are known to be involved and the clinical heterogeneity is prominent. IL-17 is important in fending off infectious agents including fungi. Patients with rheumatic diseases and in particular those with SLE are immunocompromised and deprivation of IL-17 may increase the risk for infections, including opportunistic ones. From the clinical point of view, the ranking order IL-17 blocking biologics among other biologics or disease modifying drugs remains to be determined. Specifically, we need to know if anti-IL17 biologics should be used in patients who fail established low cost medications or if they should be used as first line treatment of naïve patients or as part of combination therapy. Much more is unknown at the basic level, as IL-17 producing cells are not always contributors to inflammation. They present with a certain degree of plasticity and when found in a different environment they may even acquire regulatory features. In the whole organism T cells may move around the lymphoid organs and inflamed tissues where they may encounter conditions enabling proinflammatory or regulatory features. Moreover, despite published claims in preclinical studies and despite the success of clinical studies it has not been proven yet beyond any doubt that IL-17 can cause organ inflammation and damage on its own. For example, if a normal mouse is injected with IL-17 will it develop skin, joint or kidney disease? If IL-17 cannot do this on its own, what other mechanisms are required? The use of IL-17 deficient mice to study the role of IL-17 in the expression of disease in autoimmune models is biased by the developmental effects IL-17 deficiency may have on our immune system. Mice developing IL-17 deficiency ‘‘on call’’ are needed.

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Please cite this article in press as: Konya C et al. Update on the role of Interleukin 17 in rheumatologic autoimmune diseases. Cytokine (2015), http:// dx.doi.org/10.1016/j.cyto.2015.01.003