The Immunologic Role of IL-17 in Psoriasis and Psoriatic Arthritis Pathogenesis

Psoriasis is a chronic, immune-mediated, inflammatory disease in which genetic and epigenetic changes result in a disease phenotype characterized by altered immune function, keratinocyte activation and hyperproliferation, and the development of erythematous, indurated, scaly plaques [1‐4]. Psoriasis is driven by T cell activation associated with the secretion of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-17A, IL-22, and interferon IFN-γ [1, 5]. The IL-23/IL-17 immunologic pathway plays an especially important role in promoting disease onset and perpetuation. Data from in vitro and clinical studies indicate that IL-17A, a critical effector cytokine in this pathway, principally drives changes within affected tissues [6‐11].

Direct evidence supporting the central role of IL-17A in psoriasis includes upregulation of IL-17A and related genes in lesional and non-lesional skin of patients with psoriasis and production of IL-17A by cells associated with psoriasis [6, 8, 12]. In an in vitro study using reconstituted human epidermal sheets, IL-17A stimulated greater transcriptional activation than IL-22 or IFN-γ, correlating with the psoriasis transcriptome [13]. IL-17 also increases expression of the antimicrobial peptide LL37, a psoriasis autoantigen that promotes production of proinflammatory cytokines, and C-X-C motif chemokine ligand 1 (CXCL1) [14, 15]. This, in turn, drives expansion of ADAMTS-like protein 5 (ADAMTSLP5), another psoriasis autoantigen, causing additional expression of IL-17A and IFN-γ [15, 16].

In addition to IL-17A, the IL-17 family consists of five other members (IL-17B-F) [17‐23]. Within this family, IL-17A, IL-17C, and IL-17F are implicated in psoriasis pathogenesis as their expression is increased up to eightfold in psoriatic lesions [6, 24, 25]. Although there is more IL-17C and IL-17F in psoriatic lesions, IL-17A is the most biologically active (up to 30-fold more active than IL-17F) [10, 24]. While these three cytokines act on keratinocytes to stimulate production of proinflammatory cytokines and chemokines, the exact role of IL-17C in psoriasis pathogenesis is poorly understood [6, 25]. Despite high levels of IL-17C in psoriatic lesions, IL-17C has less impact on keratinocyte gene expression than IL-17A, IFN-γ, and TNF-α, suggesting that IL-17A is more important than IL-17C in promoting cutaneous inflammation [26].

Therapies targeting IL-17A alone are known to modulate gene expression of various cytokines and chemokines, and effectively clear psoriatic lesions [6, 27‐29]. More specifically, 2 weeks of IL-17A inhibition resulted in normalization of 765 genes, whereas TNF-α inhibition resulted in the normalization of far fewer genes (< 200) [30, 31]. In this article, the immunologic role of IL-17 in psoriasis and psoriatic arthritis (PsA) pathogenesis, including its role in innate and adaptive immunity, and the rationale for targeting IL-17A, IL-17F, and IL-17 receptor A in the treatment of psoriasis and PsA, are reviewed.

For several years, it was hypothesized that the primary source of IL-17A in psoriasis was T helper 17 (Th17) cells. Specifically, human Th17 cells differentiate from naïve T cells under the influence of TGF-β1 and proinflammatory cytokines (IL-1β, IL-6, and/or IL-21) [32, 33]. Differentiated human Th17 cells are stimulated to produce cytokines by IL-23, which also promotes the survival of Th17 cells [34, 35]. Th17 cells produce a wide variety of cytokines in addition to IL-17A, including IL-17F, IL-21, IL-22, IL-26, and TNF-α [34, 36]. Additionally, increased numbers of Th17 cells are found in the blood and affected skin of patients with psoriasis and in the blood and synovial fluid of patients with PsA [11, 37]. Recently, however, there has been a paradigm shift in the understanding of cellular sources of IL-17A in psoriasis and PsA. Increasingly, data indicate that additional important cellular sources of IL-17A are mast cells, γδ T cells, αβ T cells, and innate lymphoid cells (ILCs; Table 1) [38, 39, 47].

It was long thought that neutrophils were an abundant source of IL-17A in psoriasis; however, emerging data indicate that highly purified human neutrophils are not capable of expressing IL-17A or other IL-17 family cytokines in vitro [40, 48‐51]. Rather, IL-17A may be released from extracellular neutrophil traps, which are a central function of neutrophil host defense and inflammatory function [40, 41, 52]. Studies on this topic have yielded differing results: (1) retinoic orphan receptor (ROR)γt⁺ neutrophils expressed IL-17 mRNA, and were capable of producing IL-17 [41, 47]; (2) certain populations of bone marrow neutrophils exhibited autocrine IL-17 activity, which was driven by interactions between IL-17A and IL-17RC [53]; and (3) neutrophils in psoriatic lesions produce IL-17 [54]. Regardless of its source, neutrophil-derived IL-17 may be an early target of IL-17A inhibitors as these drugs interrupt neutrophil-keratinocyte crosstalk and disrupt the influx of neutrophils into psoriatic lesions [48].

Similarly, mast cell extracellular trap formation, induced by IL-23 and IL-1β, is associated with the release of IL-17 [40, 47]. When mast cells in healthy skin respond to trauma or microbial infection, preformed inflammatory mediators, including TNF-α, IL-17, and CXCL2, are released via degranulation or mast cell extracellular trap cell death [40]. Mast cells may also express IL-17 mRNA, produce small amounts of IL-17A, and express IL-17 receptor A [42]. Additionally, mast cells can capture, store, and release exogenous IL-17A and trigger the release of IL-17 and IFN-γ from Th1 and Th17 cells by modulating dendritic cell maturation and function [55, 56].

Neutrophils, mast cells, and other innate immune cells are also important in the pathogenesis of PsA [57]. In patients with PsA, high levels of IL-23, IL-17A, and IL-17 receptor A are present in synovial membranes, and resident Th17 cells located in entheses overexpress IL-17 and IL-22, contributing to inflammation and bone remodeling [58, 59]. Additionally, activation of the IL-23/IL-17 axis promotes production of granulocyte-colony stimulating factor, granulocyte-macrophage stimulating factor, and chemokines, including CXCL1, CXCL2, CXCL5, and CXCL8/IL-8, which promote neutrophil recruitment and migration into joint spaces [60]. Mast cell infiltration and IL-17A expression are also observed in spondyloarthritis synovial inflammation, and both mast cells and neutrophils (as opposed to T cells) are major cellular sources of IL-17 in atherosclerosis [40, 61, 62].

Elevated levels of γδ T cells, which can express RORγt, IL-23R, and C-C chemokine receptor type 6 (CCR6), are found in the dermis of psoriatic plaques as well as in the peripheral blood and synovial fluid of patients with PsA; of note, IL-17 signaling was higher in psoriatic lesional skin than in synovial tissue of patients having both skin and joint involvement [12, 63]. Stimulation of these cells with IL-23 results in production of IL-17 and IL-17 expression is observed in synovial tissue of patients with PsA [64‐66]. Dermal γδ T cell production of IL-17 is likely independent of αβ T cells; however, a CD4 and CD8 double-negative subset of αβ T cells can produce IL-17 and contribute to psoriatic skin inflammation [39]. In a murine model of psoriasis, a subset of RORγt⁺ γδ T cells form resident-memory cells in skin that rapidly produce large amounts of IL-17A/F [67]. Additionally, CCR6 is a cell surface marker of peripheral IL-17A-expressing γδ T cells [68]. IL-17A in the epidermis can induce keratinocyte expression of chemokine ligand 20 (CCL20), which, in turn, recruits IL-17A-producing CD8+ T cells (Tc17) and CCR6⁺ CD4+ T cells into skin [1, 69‐73]. CCR6⁺ cells also migrate to the epidermis or dermal-epidermal junction in response to psoriasis-triggering stimuli in murine models of psoriasis [68, 74]. In human psoriatic lesions, expression of CCR6 and its ligand CCL20 by dendritic cells and T cells has led to a hypothesis that interactions between CCR6 and CCL20 play an important role in crosstalk between dendritic cells and T cells, which ultimately causes T cell activation [75, 76]. Furthermore, synovial fluid of patients with PsA is enriched with CCR6⁺ ILCs [37, 43]. CCR6 is, therefore, being investigated as a possible new target in the treatment of both psoriasis and PsA [68, 75‐77].

ILC3s produce IL-17A and are implicated in psoriasis and PsA pathogenesis [43, 78]. Elevated numbers of ILC3s are found in lesional and non-lesional skin of patients with psoriasis, in peripheral blood of patients with psoriasis, and in synovial fluid of patients with PsA [43‐45, 78]. ILC3s express high levels of IL-17A, IL-22, CCR6, and natural cytotoxicity receptors, which are all upregulated in psoriatic lesions [43‐45, 79]. Expression of IL-17 and IL-22 in ILC3s is specifically dependent on expression and stimulation of RORγt [79, 80]. IL-23 and TNF-α also promote ILC3 differentiation [45, 79]. Interestingly, natural cytotoxicity receptor positive ILC3 levels correlate with psoriasis severity in untreated patients and decrease with anti-TNF-α therapy [45, 79]. Additionally, murine models of psoriasis indicate that ILC3s may be a rich source of non-T cell-derived IL-22 [77, 78].

Early studies on the pathogenesis of chronic inflammatory diseases, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease, led to identification of TNF-α as a key trigger of innate inflammatory pathways [31]. Although TNF-α blockers first successfully treated rheumatoid arthritis, they were quickly extended to psoriasis and PsA. Effects of TNF-α inhibition in psoriasis and PsA are complex, because therapeutic benefits likely result from indirect adaptive immune effects on the IL-23/IL-17A axis [31]. Evidence of this indirect effect was observed in clinical trials of etanercept, in which genomic data indicated that etanercept efficacy was dependent on downregulation of IL-17A or IL-17A signaling [31, 81]. The relationship between IL-17 and TNF-α is further complicated as they act synergistically to co-regulate many keratinocyte genes that are highly expressed in psoriatic skin lesions [5]. Together, these findings suggest that IL-17A and TNF-α act through distinct mechanisms to regulate downstream gene expression, with the IL-23/IL-17A axis at the core of psoriasis pathogenesis, and TNF-α playing a more ancillary role in promoting inflammation through synergism with IL-17A and through development and maturation of myeloid dendritic cells [6, 31]. This hypothesis is further supported by evidence that IL-17A inhibition alone is highly effective in psoriasis and PsA in the absence of TNF-α inhibition [7].

IL-23 and IL-17A are key inflammatory cytokines in psoriasis pathogenesis [82, 83]. IL-23 stimulates differentiation, activation, proliferation, and survival of Th17 cells that promote production of effector cytokines such as IL-17A and IL-22, but IL-17 is also produced independently of IL-23 [13, 82, 84‐86]. IL-23 injection produces psoriasis-like disease in wild-type mice, but not in IL17 knockout mice, and IL-23-mediated disease could be blocked in wild-type mice by pretreatment with anti-IL-17A antibodies [82]. This and similar evidence in other IL-23/IL-17-mediated murine disease models indicate that IL-23 is “upstream” of IL-17A, whereas IL-17A, acting “downstream,” directly affects tissue. IL-17A has a range of effects on different cellular targets within the skin and joints by promoting inflammation, coagulation, and bone/joint damage (Fig. 1) [87‐89].

Major targets of IL-17 in psoriasis include keratinocytes, endothelial cells, and innate immune cells [89]. In keratinocytes, IL-17 stimulates production of antimicrobial peptides (lipocalin 2, S100A proteins (S100A7, psoriasin), and beta defensins), proinflammatory cytokines and chemokines (IL-1β, TNF-α, IL-6, IL-17C, CXCL1, CXCL3, CXCL5, CXCL8 (IL-8), and CCL20), and proproliferative cytokines (IL-19) [5, 73, 89]. In endothelial cells, IL-17 interacts to promote tissue inflammation and procoagulant activity through upregulation of IL-6, IL-8, and intracellular adhesion molecule-1 [87, 89]. Moreover, IL-17-mediated endothelial dysfunction may contribute to development of cardiovascular comorbidities in psoriasis [89]. Although fibroblasts are not considered disease-relevant/critical target cells, they are capable of sustaining inflammation; an in vitro study showed they produce proinflammatory mediators, including IL-8, IL-1β, and IL-6 and CXCL1, CXCL2, CXCL3, CXCL5, and CXCL6, in response to IL-17 [13]. Lastly, IL-17A has proinflammatory effects on antigen-presenting cells, including macrophages [90].

The centrality of IL-23 and IL-17A to psoriasis and PsA pathogenesis has resulted in many new biologic therapies targeting these cytokines (Table 2) [98, 99]. These drugs, however, can have notable clinical differences related to dosing and safety profiles. Therapies targeting cytokines further upstream in this pathway require less-frequent dosing to maintain efficacy than drugs targeting more downstream cytokines and receptors [100]. IL-23 and IL-12/23 inhibitors (furthest upstream) require maintenance dosing every 8–12 weeks, whereas maintenance dosing with approved IL-17A inhibitors (midstream) is required every 4 weeks, and the IL-17 receptor A antagonist brodalumab (furthest downstream) is administered every 2 weeks [98, 101]. Mechanistic studies indicate that IL-17A has both protective and proinflammatory effects in the gut. There is strong evidence to support the role of γδ T cell-derived IL-17A in the protection of epithelial barriers in the intestinal mucosa; as such, IL-17A blockade may exacerbate inflammatory bowel disease [102‐106]. Additionally, IL-17A production has been observed in subpopulations of T regulatory cells, and it is hypothesized that these cells may be protective against inflammatory bowel disease [107, 108]. Pooled safety data from clinical trials of ixekizumab and secukinumab, however, show that exacerbation of inflammatory bowel disease rarely occurs with IL-17A inhibition [109‐111]. Nonetheless, IL-17A inhibitors should be used with caution in patients with a history of inflammatory bowel disease [112]. IL-17A blockers are also associated with increased risk for mucocutaneous candidiasis (< 5% of treated patients) because IL-17 is important in the control of Candida albicans infections within skin and mucosa [99, 113]. Thus, patients being treated with IL-17A blockers should be screened regularly for signs of mucocutaneous candidiasis; in the small percentage of patients who develop these types of infections, treatment with topical or oral antifungal therapy is generally effective and discontinuation of anti-IL-17A therapy is not necessary [113]. In phase 3 psoriasis trials of brodalumab, psychiatric adverse events, including depression, anxiety, and suicidal ideation and behavior, were observed, suggesting a possible safety concern [114]. However, analysis of data across five clinical trials did not find a causal relationship between treatment with brodalumab and suicidality; rates of adverse events of suicidal ideation and behavior were similar with brodalumab, placebo, and ustekinumab [114]. Patients with psoriasis are known to be at increased risk for psychiatric comorbidities, and all patients with suicidal ideation who received brodalumab had underlying psychiatric disorders or stresses [115]. Of note, similar safety signals have not been observed with either secukinumab or ixekizumab [116].

An important issue in managing psoriasis is recurrence of lesions after treatment discontinuation, which is linked with a residual disease genomic profile [117‐119]. Relapses may be caused by residual tissue-resident memory T cells not being fully eradicated with anti-TNF therapy. In an etanercept trial, a subset of inflammatory genes that contribute to psoriasis pathogenesis, including IL-12p35, IL-22, IL-17, and IFN-γ, did not return to non-lesional levels [117, 118]. Particularly, clinical recurrences at the same body areas may be determined by the marked presence of IL-17A-producing αβ T cell clones in post-treatment-resolved psoriatic lesional skin, which produce eightfold more IL-17A than αβ T cell clones in healthy skin [120].

Given the critical role of IL-17A in psoriasis pathogenesis, it is not surprising that the IL-17A inhibitors secukinumab and ixekizumab are associated with complete or near complete skin clearance in many patients and have demonstrated efficacy that is superior to many other agents (i.e., TNF-α inhibitors and ustekinumab) [27, 95, 121]. In patients with psoriasis, IL-17A inhibition by secukinumab normalizes levels of dysregulated proteins, including IL-1β, IL-8, IL-1 receptor antagonist, myeloperoxidase, antimicrobial peptides (β-defensin 2 and lipocalin 2), matrix metalloproteinase-1, matrix metalloproteinase-8, matrix metalloproteinase-9, and the chemokines CXCL1, CXCL5, and CCL20 [122, 123]. Secukinumab also decreases mRNA levels of antimicrobial peptides, chemokines, IL-36α, IL-36β, IL-36γ, IL-36RN, IL-17A, and IL-17F [122]. Additionally, ixekizumab normalizes > 3 times more genes than etanercept after 2 weeks [30, 31]. Targeting IL-17 receptor A with brodalumab is also highly effective and inhibits signaling induced by IL-17A, IL-17F, IL-17E (IL-25), and IL-17A/F [97, 124, 125]. Brodalumab also normalizes psoriatic lesional skin transcriptome, the gene expression profile associated with IL-17A, IL-17C, and IL-17F, and reduces IL-23 levels along with keratinocyte-derived mediators of inflammation, including chemokines, IL-36A, and S100s [125]. More recently, bimekizumab, a monoclonal antibody targeting IL-17A and IL-17F, demonstrated high efficacy in psoriasis [96]. Whether this is due to the highly effective blockade of IL-17A or combined effects of blocking 2 IL-17 isoforms is unclear. Interestingly, studies indicate the blockade of both IL-17A and IL-17F decreases inflammation more than the inhibition of IL-17A alone [126‐128].

Although the IL-17A gene signature is higher in skin from patients with PsA compared with joints, IL-17A is thought to play a key role in PsA pathogenesis, acting on synovial-like joint fibroblasts, osteoblasts, and osteoclast precursors to promote inflammation and joint damage [12, 129]. Specifically, IL-17A, TNF-α, IL-23, and other inflammatory cytokines activate the innate immune regulators, nuclear factor κB (NFκB), and its receptor activator/ligand (RANK/RANKL). NFκB and RANKL upregulation triggers transcription of genes that promote secretion of bone matrix-degrading enzymes, including matrix metalloproteinase-9, tartrate-resistant acid phosphatase, and cathepsin K [60, 130, 131]. The IL-17A inhibitors secukinumab and ixekizumab are approved for PsA based on phase 3 data (FUTURE 1 and FUTURE 2 for secukinumab, SPIRIT-P1 and SPIRIT-P2 for ixekizumab) [132‐135]. These studies demonstrated that treatment with IL-17A blockers improved joint and skin signs and symptoms of PsA, along with physical functioning and quality of life, compared with placebo [132‐135]. Finally, a phase 2 study of brodalumab in PsA provided improvements in joint and skin symptoms and physical functioning (with higher doses) compared with placebo [136].

IL-17 also promotes vascular inflammation, endothelial dysfunction, coagulation, thrombosis, and arterial hypertension. Correspondingly, elevated serum IL-17 has been observed in patients with acute myocardial infarction, and monoclonal antibodies that neutralize IL-17 may improve outcomes in patients with psoriasis and/or PsA and comorbid cardiovascular disease [137, 138]. This hypothesis is further supported by a murine model of atherosclerosis; inhibition of IL-17A led to prevention of lesion progression and induction of plaque stabilization in advanced lesions [90]. In a murine model of IL-17A overexpression, neutralization of cytokines downstream of IL-17A improved vascular health [139]. Additionally, anti-IL-17A monoclonal antibodies prevented vascular disease in a murine model of psoriasis [140]. In humans, an acute myocardial infarction registry demonstrated that serum IL-17A below a median of 6.26 pg/mL was associated with higher risk for all-cause mortality and recurrent myocardial infarction, but many patients had IL-17A levels below the assay’s detection limit of 2.5 pg/mL [141]. To more directly study this issue in moderate-to-severe psoriasis, Gelfand and colleagues are assessing whether treatment with secukinumab can lead to improvements in aortic inflammation (VIP-S, NCT02690701), a well-established biomarker of atherosclerotic cardiovascular disease.

Many cytokines are involved in psoriasis development; however, data identify IL-17A as the major effector cytokine driving pathogenesis. IL-17 is produced by many cell types, acts on a range of cellular targets in tissue and immune cells, and plays important roles in innate and adaptive immunity. Inhibition of IL-17A, IL-17 receptor A, or simultaneous inhibition of IL-17A and IL-17F leads to disruption of signaling pathways critical to the development and maintenance of psoriasis. Accordingly, biologics that target IL-17A function lead to rapid and dramatic improvement of skin and joint symptoms in psoriasis and PsA.