Opinion
IL-23: A Promising Therapeutic Target for Systemic Lupus Erythematosus

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Cytokine-mediated immunity plays a crucial role in the pathogenesis of various autoimmune diseases including systemic lupus erythematosus (SLE). The recent identification of the dimeric interleukin (IL)-12-related cytokine IL-23 now contributes to our understanding of the fine-tuning of cellular immunity. The critical implication of IL-12 p40 in autoimmune inflammation has long been misinterpreted and until recently have studies revealed that it is IL-23, not IL-12, is the crucial factor in this immune dysregulation. Therefore, targeting of IL-23 or the IL-23 receptor is a potential therapeutic approach for autoimmune diseases including SLE. In this opinion article, we will discuss the biological features of IL-23 and summarize recent advances on the role of IL-23 in the pathogenesis and treatment of SLE.

Introduction

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of multiple autoantibodies, complement activation and immune-complex deposition, resulting in tissue and organ damage. At present, the etiology and pathogenetic mechanisms of SLE are still unclear. Epidemiological data suggest that SLE may be a result of a combination of genetic and environmental factors with a prominent autoimmune component.

It has been confirmed that cytokines play a pleiotropic role in the pathogenesis of SLE (1). Recent studies have revealed that interleukin 23 (IL-23) rather than IL-12 is regarded as a crucial cytokine for the pathogenesis of autoimmune diseases 2, 3 including experimental autoimmune encephalomyelitis (EAE) (4), collagen-induced arthritis (CIA) (5), psoriasis (6), and inflammatory bowel disease (IBD) 7, 8. IL-23 plays a key role in the development of pathogenic Th17 cells that produce the cytokine IL-17 9, 10, 11. IL-17 induces the production of several proinflammatory cytokines such as tumor necrosis factor α (TNFα) and IL-6, chemokines, and metalloproteinases from various tissues and cell types and recruits neutrophils to tissues 12, 13, which are implicated in the pathogenesis of SLE and other autoimmune diseases (2). IL-23 is a heterodimeric cytokine comprising IL-12 p40 and IL-23 p19 subunits. It is expressed predominantly by activated dendritic and phagocytic cells 14, 15. IL-12 and IL-23 share a common p40 subunit binding to common IL-12 receptor β1. The high-affinity IL-23 receptor complex comprises a common IL-12 receptor β1 and an IL-23 receptor (IL-23R), which is preferentially expressed on activated/memory T cells, T-cell clones, and natural killer cell lines in humans (15).

The association of IL-23R polymorphisms have been revealed in many autoimmune diseases such as IBD (7) and ankylosing spondylitis (AS) 16, 17. IL-23R has now been proposed as a common genetic marker for a variety of autoimmune diseases.

Considering the central role that IL-23 plays in the pathogenesis of various autoimmune disease, studies focusing on its role in SLE have been arising in recent years. This opinion article will discuss the biological features of IL-23 and summarize recent advances on the role of IL-23 in the pathogenesis and treatment of SLE.

It was shown that IL-12 shares the p40 subunit and the IL-12Rβ1, as well as components of the signaling transduction pathways, with IL-23 (18). The p40 expression is primarily restricted to antigen-presenting cells (APCs) such as monocytes, macrophages and dendritic cells (DCs) (19). A p19 protein that combines with IL-12p40 to form a novel, biologically active cytokine designated IL-23, has been identified and this has functions similar to, but discrete from, IL-12 20, 21. P19 is also produced by APCs as well as by T-cells and endothelial cells. At the sequence level, p19 is most closely related to the IL-12p35 subunit. Moreover, this similarity extends to functional characteristics because p19 forms a disulfide-linked heterodimer with the IL-12p40 subunit (22). In mice, Th17 differentiation is dependent upon TGF-β and IL-6, whereas recent reports suggest that IL-23, pro-inflammatory cytokines and TGF-β are all required for differentiation of mature human Th17 cells from naive cord blood cells. This is in contrast to previous studies that used adult cells, suggesting that IL-23 was sufficient for IL-17 induction 23, 24. In spite of this, it remains easy to obtain a consensus that IL-23 may plaly a key role in Th17 development.

IL-23 exerts its biological activities through the interaction with a heterodimeric receptor complex composed of IL-12Rβ1 and IL-23R (one subunit of IL-23 receptor) 15, 25. The IL-23R gene is located on the short arm of chromosome 1 at position 31.3 (7) and is expressed on various cell populations. In addition to activated and memory T cells, IL-23R expression on hematopoietic cells includes NK cells, NK T-cells, eosinophils, dendritic cells, and macrophages 4, 21, 25, 26. Furthermore, IL-23R is expressed on epithelial cell populations such as keratinocytes, where it can contribute to induction of antimicrobial peptide production (27). IL-23 can directly bind the IL-12Rβ1 chain through its interaction with the IL-12p40 subunit. IL-23 requires IL-23R as a heterodimeric partner to allow signal transduction to occur. However, the precise function of IL-23 in Th17 biology remains elusive.

The interaction of IL-12 with its high-affinity receptor induces phosphorylation of janus kinases (JAKs), and the cellular effects of IL-12 are primarily mediated by signal transducer and activator of transcription (STAT) 4 phosphorylation (28). The binding of IL-23 to its receptor complex also leads to activation of JAKs and phosphorylation of STAT4. However, IL-23 induces less phosphorylation of STAT4 than IL-12. Moreover, upon IL-23 stimulation, activated STAT4 heterodimerizes with STAT3 to a large extent (25). Two other cytokines were thought to be involved in Th17 differentiation. IL-6 and IL-21 also share the STAT3-dependent signaling pathway with IL-23 (29). Indeed, in mice STAT3 is absolutely required for the induction of IL-17, IL-17F, and RORγt 30, 31, 32. Moreover, transduction of human cord blood CD4+ T cells with RORγt is sufficient to induce IL-17 production, and conversely, knockdown of RORγt results in much lower IL-17 production. Meanwhile, RORα, another ROR family member, also induces IL-17 expression when overexpressed in primary human T cells (33). Collectively, these evidences suggested that IL-23 may active STAT3 and RORγt signal pathyway and finally contribute to hyperproduction of IL-17 and other cytokines.

As we know, the situation in autoimmune and inflammatory diseases comes with a high degree of complexity. Pène et al. isolated CD4+ T cells from lesions of patients suffering from chronic autoimmune diseases including psoriasis, Crohn's disease (CD), and rheumatoid arthritis (RA) and identified Th1 and Th2, as well as Th17 cells, in inflamed tissues (34). As described above, IL-12/Th1 and IL-23/Th17 axis require different signal pathways. Cytokines produced by these Th cells may be involved in the different phenotype of SLE and other autoimmune diseases.

Models of human autoimmune disease including EAE and CIA have been recognized as prototypic CD4+ Th1-cell-mediated diseases. For example, IFN-γ producers are found in the brains of mice during EAE, inhibition of T-bet expression by RNA interference ameliorates EAE, and IFN-γ has been described for its pathogenic role in different mouse models of inflammation 35, 36, 37, 38. Nevertheless, a new line of evidence favors a role of IL-23/Th17 rather than IL-12/Th1 pathway during the pathogenesis of autoimmune disorders, e.g., mice lacking IL-23p19 but not IL-12p35 were shown to be resistant to EAE and CIA. Administration of anti-IL-23p19 monoclonal antibody (mAb) or anti-IL-12p40 mAb inhibited the production of multiple inflammatory cytokines, including IL-17, IL-6, IFN-γ, IL-1β and TNF-α. Moreover, adoptive transfer of myelinoligodendrocyte-specific, IL-17-producing T cells, but not IFN-γ-producing T cells, induced EAE in recipient mice. Consistent with the role of the Th17 lineage in autoimmune inflammation, IL-17-deficient mice either were resistant to EAE and CIA induction or showed reduced disease severity (39). Furthermore, genetic studies revealed an association between IL-23R genes and susceptibility to several autoimmune diseases including CD, RA and Graves' ophthalmopathy (40). Collectively, the IL-23–Th17 axis, rather than the IL-12–Th1 axis, is crucial to autoimmune disease development.

It has been confirmed that cytokine-mediated immunity plays a crucial role in the pathogenesis of SLE. Recent studies have explored the role of IL-23 in SLE, and their results indicated that IL-23 produced by abnormal APC cells may be involved in the pathogenesis of SLE. Zhang et al. reported that double-negative T cells from MRL/lpr mice express high amounts of IL-17 and that as disease progressively worsens, the expression of IL-17 and of IL-23 receptor in lymphocytes from these mice increases. Lymph node cells from lupus-prone mice, but not control mice, treated in vitro with IL-23 induce nephritis when transferred to non-autoimmune, lymphocyte-deficient Rag-1−/− mice. Kidney specimens from these recipient mice showed significant Ig and complement deposition. In addition, lupus-prone mouse T cells express high levels of IL-23 receptor mRNA and IL-17A mRNA and protein. Incubation of the cells with IL-23 leads to a further significant increase in both IL-23 receptor and IL-17A expression. Data indicate that an aberrant activation of IL-23/IL-17 axis contributes to the development of nephritis in lupus-prone mice (11). Sutton et al. provided evidence that γδ T cells, through IL-17 and IL-21 production, may help mediate the effects of IL-23 and IL-1β in promoting the development and expansion of Th17 cells. Thus, analogous to the role of NK cells in amplifying the effects of IL-12 on Th1 cells, γδ T cells may act to amplify the induction of Th17 cells. Their findings provide important new information on the pathogenic role of IL-23 and underline the importance of targeting this cytokine in the development of new therapeutic interventions against autoimmune diseases (41).

In fact, in addition to these implications from animal experiment, some studies in human SLE also indicated need to target on IL-23 and its receptor. Cheng et al. reported that decreased plasma IL-22 levels, but not increased IL-17 and IL-23 levels, correlate with disease activity in SLE patients (42). Interestingly, studies revealed that IL-22 is also involved in IL-23 signalling pathway 43, 44. Wong et al. found that ex vivo inductions of IL-17 by IL-23 or IL-18 from co-stimulated lymphocytes were significantly higher in SLE patients than controls, and elevated IL-12, IL-17 and CXCL10 concentrations correlated positively and significantly with SLEDAI (45). Moreover, Huang et al. found that the mRNA levels of p19, p40 of the PBMC in active SLE patients were significantly higher compared with those in the inactive SLE patients (46). Except for IL-17 and IL-22, IL-23/IL-23R axis may also be responsible for other pro-inflammatory cytokines. Hillyer et al. reported that IL-23R blockade results in a significant inhibition of TNF-α (57%), IL-1β (51%) and IL-6 (30%) in RA synovial cultures (47).

More recently, Kwan et al. quantified the mRNA expression of IL-17, IL-23 and other Th17-related cytokines in the urinary sediment of subjects with active SLE, with history of lupus nephritis in remission, no history of renal involvement SLE and healthy subjects. They found the urinary expression of Th17-related genes was increased in SLE patients. The degree of upregulation, however, was inversely associated with systemic and renal lupus activity. For example, urinary expression of IL-17 was inversely correlated with the SLEDAI score. For patients with active lupus nephritis, the histological activity index of kidney biopsy was also inversely correlated with the urinary expression of IL-17 and IL-23 (48). These findings suggest a regulatory role of IL-23 in the pathogenesis of SLE. As described above, the previous studies regarding the association of IL-23 with SLE disease activity were somewhat different. It is possible that there is retention of IL-23 within the tissues or organs in patients with active SLE, resulting in reduction in urinary or peripheral blood expression in the presence of high disease activity.

However, current available studies demonstrated no association of IL-23A or IL-23R polymorphisms with susceptibility to SLE in several populations including Spanish (49) and Korean (50). In spite of this, it should be noted that the level of IL-23 was not examined directly. Furthermore, differences in ethnicity may lead to the conflicting results for the association between IL-23 and SLE. Thus, further studies with large samples in different populations are needed to confirm the association between IL-23 and SLE.

Presently, there is increasing evidence in both humans and mouse models that IL-23 play a role in SLE development and progression. The differences of IL-23 plasma or mRNA expression between treated and untreated SLE patients may suggest the possibility of using anti-IL-23 therapy to treat the subset of SLE patients that are characterized by high levels of IL-23. In fact, exciting discoveries on the effects of targeting IL-23 in autoimmune diseases have recently been made. Administration of anti-p40, which blocks both IL-23 and IL-12 activities, induced clinical responses and remissions in patients with active CD and treatments were associated with decreases in Th1-mediated inflammatory cytokines at the site of disease (51). In addition, Chen et al. reported that anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis (52). All these results indicated that specific blockade of the IL-23 immune pathway may be an effective and safer therapy for autoimmune inflammatory diseases including SLE. With findings obtained in eventual studies, development of recombinant IL-23 engineered to last long in vivo, discovery of small chemical compounds that mimic IL-23/IL-23R signaling for immunosuppression and establishment of antagonistic as well as agonistic anti-IL-23 antibodies will contribute to the development of novel therapeutic approaches to manage SLE and other autoimmune diseases. However, several points should be realized. First, because both the IL-23/IL-23R is critical in mediating antimicrobial defenses and cross-regulating other cell subsets, risk of infectious complications and regulation of other immune cell subsets need to be considered. Second, much of the data regarding IL-23 have been obtained from murine models, which may not be applicable to human SLE. Therefore, further studies are required, especially in human systems, to comprehensively explore the therapeutic potential of IL-23 in SLE.

SLE, however, is a complex disorder that probably entails multiple different perturbations in the immune system leading to a manifestation of autoimmune inflammation. Therefore, as we develop an understanding of the genetic, immune, and environmental mechanisms leading to SLE in a given individual, we should be able to better target the specific inflammatory pathway mediating disease in that individual.

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Acknowledgments

This work was partly supported by grants from the National Natural Science Foundation of China (30830089, 30771848).

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