Abstract
Axial spondyloarthritis (axSpA) is comprised of ankylosing spondylitis (AS) and non-radiographic axSpA. In recent years, the involvement of the interleukin (IL)-23/IL-17 axis in the pathophysiology of axSpA has been widely proposed. Since IL-23 is an upstream activating cytokine of IL-17, theoretically targeting IL-23 should be effective in axSpA, especially after the success of the treatment with IL-17 blockers in the disorder. Unfortunately, IL-23 blockade did not show meaningful efficacy in clinical trials of AS. In this review, we analyzed the possible causes of the failure of IL-23 blockers in AS: 1) the available data from an animal model is not able to support that IL-23 is involved in a preclinical rather than clinical phase of axSpA; 2) Th17 cells are not principal inflammatory cells in the pathogenesis of axSpA; 3) IL-17 may be produced independently of IL-23 in several immune cell types other than Th17 cells in axSpA; 4) no solid evidence supports IL-23 as a pathogenic factor to induce enthesitis and bone formation. Taken together, IL-23 is not a principal proinflammatory cytokine in the pathogenesis of axSpA.
Introduction
Axial spondyloarthritis (axSpA) comprised of ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA) is an inflammatory disease of the axial skeleton. Historically, therapies of AS have been limited to mainly physiotherapy and non-steroidal anti-inflammatory drugs (NSAIDs), while conventional immunosuppressants or disease-modifying anti-rheumatic drugs may only be helpful in concurrent peripheral joint involvement. In the last two decades, the major therapeutic breakthrough has been the advent of biologic drugs TNF inhibitors (TNFi), which have shown good efficacy in patients who were non-responders or insufficient responders to NSAIDs, with reduction of pain, stiffness, and physical handicap. However, up to 40% of axSpA patients do not demonstrate a meaningful clinical response to TNFi, and some patients lose response during treatment (secondary therapeutic failure) (1). Further, TNFi may be contraindicated for certain patients. So there is still a need for an additional class of biologic.
The discovery of the interleukin (IL)-23/IL-17 pathway revealed key molecules involved in the pathophysiology of axSpA. When IL-23 binds to its receptor IL-23R, the complex recruits JAK2 and Tyk, members of the Janus family of tyrosine kinases, which in turn mediate the activation of the IL-23/IL23R and, eventually, the phosphorylation of the downstream STAT3 (2). IL-23 stimulates the differentiation and expansion of Th17 cells via IL-23R and induces the release of molecules such as IL-17 or IL-22, eventually activating the “effector cells” keratinocytes (3, 4), B cells, osteoclast precursors, and macrophages (5, 6). Mounting evidence demonstrates that the IL-23/IL-17 axis appears to be one of the main pathways involved in the development of axSpA. It is reasonable that the inhibition of IL-23 and IL-17 should be an alternative choice for the treatment of axSpA.
Clinical trials performed with the IL-17-blocking monoclonal antibodies secukinumab, ixekizumab, bimekizumab, and netakimab have clearly shown significant reductions in the signs and symptoms of patients with radiographic axSpA or AS (7–10) and of patients with non-radiographic axSpA (11, 12). Furthermore, long-term treatment with secukinumab retarded structural progression in AS (13).
But drugs blocking IL-23 lacked efficacy in the treatment of axSpA. For instance, ustekinumab, an IL-12/IL-23 inhibitor, was assessed in axSpA in three trials, but the latter two were discontinued because of failure in the first trial (14). Risankizumab, an IL-23p19 inhibitor, failed in AS to meet the primary endpoint (15). The converse efficacy of IL-17A inhibition and IL-23 inhibition in AS suggests that IL-17A rather than IL-23 is the major cytokine mediating disease pathogenesis in axSpA. Targeting the two members of the IL-23/IL-17 axis, both anti-IL-17 and anti-IL-23 treatment have shown beneficial effects in psoriasis and PsA (16–18), while IL-17 inhibitors rather than IL-23 inhibitors are effective in axSpA. Here, we discussed the possible causes for the therapeutic failure of IL-23 inhibition in axSpA.
Is IL-23 Involved in Initiation Rather Than Perpetuation of Axial Spondyloarthritis?
IL-23 is primarily secreted by antigen-presenting cells such as macrophages and dendritic cells and along with other cytokines including IL-1 and IL-6 in tissues like the skin, intestinal mucosa, lungs, synovium, and brain. IL-23 expression is induced by stimulation of myeloid-derived cells with pathogen ligands, as well as other mediators such as prostaglandin E2 and proinflammatory cytokines. IL-23 is a pleiotropic cytokine critical for the differentiation, survival, and expansion of conventional (αβ) T cells and unconventional (γδ) T cells (19), which regulate a plethora of immune responses, and it can promote the polarization to IL-17-expressing cells.
Some researchers believed that one of the possible reasons why IL-23 inhibitors are ineffective in axSpA may be that IL-23 is pivotal for the initiation of disease but not involved in ongoing or persistent inflammation (6, 20–22). The HLA-B27/Huβ2m transgenic rats were immunized with heat-inactivated Mycobacterium tuberculosis to induce an experimental SpA model. By using the SpA model, van Tok et al. (20) reported that treatment with anti-IL-23R before the signs of arthritis/spondylitis onset could completely inhibit the development of spondylitis and peripheral arthritis, whereas treatment with anti-IL-23R 1 week after 50% arthritis incidence failed to reduce the incidence and the severity of experimental SpA. In contrast, anti-IL-17 treatment suppressed arthritis/spondylitis in both the initiating phase and established phase of the same SpA model and inhibited the periosteal new bone formation (23, 24). So these data seem to support that axSpA might be IL-23-dependent in the initiation of the disease but IL-23-independent once the disease is established, which is different from IL-17.
Collagen-induced arthritis (CIA) is a classical model of experimental arthritis mimicking rheumatoid arthritis (RA), which is characterized by synovitis, cartilage destruction, and bone erosion. In CIA mice, IL-23p19 knockout protected the mice to develop clinical signs of disease and completely inhibited the development of joint and bone pathology (25). Neutralizing anti-IL-23p19 antibody (anti-IL23p19) treatment before the signs of arthritis onset significantly decreased arthritis score and histological severity in CIA mice, but the treatment lost the inhibitory effects when given after the onset of arthritis (26). These data also indirectly support that IL-23 only plays a pathological role in the initiating phase of inflammatory arthritis. However, IL-23p19 knockout did not prevent the onset of joint inflammation in a murine model of antigen-induced arthritis (27). Polyclonal anti-IL-23 antibody treatment after the onset of arthritis significantly decreased paw volume, synovial tissue inflammation, and bone destruction in CIA rats in a dose-dependent manner (28). These data do not support the above hypothesis that IL-23 may only play a pathogenic role in initiating arthritis.
Although animal models are widely used to test potential new therapies, there is no ideal animal model with high predictive values of therapeutic efficacy in human axSpA. It is easier for a compound/agent to exert beneficial efficacy in experimental arthritis than human arthritis. Moreover, it is easier to show the efficacy of protective treatment than therapeutic treatment in animal models of arthritis. For example, there are a huge amount of compounds to be demonstrated to have prophylactic efficacy to inhibit the development of arthritis in CIA models, including dietary ingredients/supplements (e.g., resveratrol, docosahexaenoic acid, and salmon proteoglycan) (29–31), countless herb extracts (e.g., Acanthopanax senticosus Harms extract, aqueous extract of Trachyspermum ammi seeds, and Glycine tabacina ethanol extract) (32–34), anti-inflammatory agents (e.g., ibuprofen, celecoxib, etodolac, indomethacin, and dexamethasone) (34–36). Vascular endothelial growth factor (VEGF) is a growth factor with important pro-angiogenic activity. Neutralizing anti-VEGF mAb was demonstrated to have prophylactic but not therapeutic actions in CIA mice (37). We cannot take for granted that these data support that VEGF is only involved in the initiation rather than persistence of RA. Since other studies demonstrated that expression levels of VEGF mRNA and protein were associated with severity of arthritis in CIA mice (38), clinical data supported that VEGF plays a pivotal role in the pannus formation/angiogenesis in rheumatoid synovium (39).
Evidence shows that a compound’s therapeutic efficacy rather than prophylactic efficacy in both CIA and adjuvant-induced arthritis (AIA) models has a more predictive value of clinical efficacy in patients with RA than efficacy from either model alone (40). IL-17 deficiency markedly suppressed joint inflammation and destruction in both CIA and streptococcal cell wall-induced arthritis models (41, 42). IL-17A gene transfer exacerbated synovial inflammation and bone loss before noticeable joint swelling was established in CIA mice (43). Both preventive and therapeutic treatments with IL-17 blockers (i.e., neutralizing anti-IL-17 antibody, IL-17 receptor IgG1 Fc fusion protein, and vaccination against IL-17) resulted in reduced chronic inflammation and cartilage degradation in both CIA and AIA models (44–47). Based on these data from the 3 animal models, can we draw a conclusion that IL-17 plays a pivotal role in both initiating phase and ongoing phase of RA? Of course, it is not true, since numerous clinical studies confirmed that RA patients failed to exhibit a satisfactory response to neutralization of IL-17/IL-17 receptor (i.e., secukinumab, ixekizumab, and brodalumab) (48–51).
Taken together, the available data from one animal model are not able to support that IL-23 is involved in an initiating rather than ongoing phase of axSpA.
Th17 Cells Are Not Principal Inflammatory Cells in the Pathogenesis of Axial Spondyloarthritis
In 2005, two groups independently discovered a new specific subset of CD4+ T cells, Th17 cells, which mainly produce IL-17 (52, 53). Except for IL-17, Th17 cells also produce IL-22 and certain other proinflammatory cytokines.
IL-23 significantly enhanced IL-17 secretion (54), and Th17 cells were absent in IL-23-knockout mice (55). These data imply that IL-23 is critical for Th17 cell development or survival. Later studies discovered the combination of IL-6 and transforming growth factor (TGF)-β induced transcription factor RORγt in naïve T cells and upregulated IL-23R expression (56). IL-23/IL-23R signaling plays an important role in the stabilization of the Th17 phenotype and expansion of Th17 cells (56). In human CD4+ T cells, IL-1β induced differentiation of Th17 cells, and IL-6 further enhanced the differentiation (57). So the differentiation, expansion, and stabilization of human Th17 cells depend on the presence of TGF-β, IL-23, IL-6, and IL-1β (58). Thereafter, the IL-23/IL-17 axis has been attracting a lot of attention in inflammatory disorders, including axSpA (59).
The finding from genome-wide association studies (GWAS) was a major stimulus to consider the importance of Th17 cells in axSpA or AS, which demonstrated that polymorphisms in multiple genes of those cytokines and their signaling pathways are involved in the Th17 pathway, such as IL-23R, IL-12B (encoding p40 of IL-23 and IL-12), IL-1R2, IL-6R, and RUNX3 (60, 61). In 2008–2009, increased proportions of Th17 cells in peripheral blood were found in AS patients (62, 63). Moreover, the protective effect to develop AS was found in the carriers with R381Q IL23 receptor polymorphism, resulting in a lower percentage of circulating Th17 cells (64, 65). All these data indirectly support that Th17 cells play an important role in the pathophysiology of AS. However, the evidence from clinical trials to block the cytokines in the differentiation or expansion of Th 17 cells is disappointing. As discussed above, IL-23 inhibition with both ustekinumab targeting IL-23p40 and IL-12p40, and risankizumab targeting IL-23p19, failed to exert significant efficacy in AS (14, 15). Neither tocilizumab, a humanized monoclonal antibody against IL-6 receptor, nor sarilumab, a fully human monoclonal antibody anti-IL-6R, showed satisfactory efficacy in patients with active AS or SpA (66, 67). IL-1 inhibition with anakinra, a recombinant IL-1 receptor antagonist, failed to show satisfactory improvement in AS either (68).
These data imply that Th17 cells are not principal inflammatory cells in the pathogenesis of axSpA, which does not mean that IL-17 is not a principal proinflammatory cytokine in axSpA, because Th17 cells are not the sole cell source of IL-17 (3).
IL-17 Can Be Produced by Several Immune Cell Types Other Than Th17 Cells in Axial Spondyloarthritis Independently of IL-23
The IL-17 superfamily consists of six members (IL-17A to IL-17F). IL-17A and IL-17F are the two members with the highest sequence homology to each other (50%) and share similar actions. IL-17 acts on many cell types including T cells themselves. In inflammatory arthritis, IL-17A can induce the production of IL-1β, IL-6, TNF-α, C-C motif chemokine ligand 2 (CCL2), matrix metalloproteinases (MMPs) (including MMP1, MMP9, and MMP13), and receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) from target cells, thereby perpetuating the inflammation, driving the degradation of extracellular matrix, and inducing bone erosion within the joint. IL-17 also promotes angiogenesis, thus increasing blood flow and facilitating the influx of inflammatory cells into the inflamed joint [reviewed in (69)].
Increased expression of IL-17A was found in the synovial fluid and/or serum from patients with active AS (70). In AS facet joints, the significantly increased frequency of IL-17-secreting cells was demonstrated (71). These data suggest that IL-17 might participate in the pathophysiology of AS.
However, immunohistological analysis further revealed that the majority of IL-17(+) cells in AS facet joints were neutrophils, while CD3+ T cells and AA-1+ mast cells were less often IL-17-positive (71). No significant difference in the frequency of Th17 cells in the blood was found between axSpA patients and healthy controls (71). These data suggest that Th17 cells might be not the major source of IL-17 in axSpA/AS, although IL-17 was first thought to be secreted by CD4+ Th17 cells.
Recently, IL-17 has been demonstrated to be produced by lymphocytes of both the adaptive and innate immune systems. Aside from Th17 cells, IL-17-producing CD8+ T cells (Tc17) also produce IL-17 (72). During an inflammatory response, much of the IL-17 is produced by innate immune cells, including γδ T cells (73), mucosal-associated invariant T (MAIT) cells (74), natural killer (NK) cells (75, 76), invariant NK T (iNKT) cells (77), type 3 innate lymphoid cells (ILC3) (78), lymphoid tissue inducer (LTi) cells (79, 80), and neutrophils (81). RORγt, the master transcriptional regulator of Th17 cells, is also expressed by IL-17-producing innate-like T cells, such as iNKT and γδ T cells (82).
Increased levels of conventional CD8+ Tc17 cells were found in the blood of AS patients, and the proportion of Tc17 cells positively correlated with the disease severity of AS. AS patients had a lower frequency of γδ T cells and MAIT cells in the peripheral blood but had an elevated frequency of IL-17A+ MAIT cells in blood as compared with healthy controls (83–85). Compared with RA, there are more enriched IL-17A+ MAIT cells in the synovial fluid of AS (83, 84). Expression of a MAIT cell activation marker CD69 on IL-17A+ MAIT cells was correlated with the Ankylosing Spondylitis Disease Activity Score (ASDAS) in patients with AS (84). In normal human spinous processes, entheseal soft tissue, and peri-entheseal bone, entheseal γδ T cells with the phenotype of Vδ1 and Vδ2 subsets were confirmed immunohistochemically (86). IL-17-producing ILC3 cells were expanded in the blood, synovial fluid, gut, and bone marrow of patients with AS (87). Increased IL-17+ NK, γδ T, and ILC3 cells in peripheral blood and synovial fluid were found in patients with reactive arthritis, enteropathic SpA, and undifferentiated SpA (88, 89). All these data support that the IL-17-producing cells may be involved in the pathophysiology of SpA. Furthermore, upregulation of IL-17 in AS MAIT cells was not dependent on priming with IL-23 (83). In γδ T cells, the production of IL-17A was also IL-23-independent (86, 90).
Taken together, IL-17 may be produced independently of IL-23 in the immune cells other than Th17 cells in axSpA.
IL-23 Overexpression Is Not Sufficient to Induce Enthesitis and Bone Formation
IL-23 plays a key role in amplifying and maintaining IL-17 production in many cells. Monocytes and dendritic cells are the primary cells releasing IL-23. A CD14+ myeloid population (monocytoid cells) in the human enthesis was found to produce IL-23, IL-1β, TNF, and CCL20 (91). In the facet joints of patients with AS, IL-23-positive cells were found to be increased in the subchondral bone marrow, but not increased in fibrous tissue (92). In 2007, IL-23R gene polymorphisms were first revealed as risk factors for developing AS (93). In 2012, IL-12B (encoding p40 of IL-23 and IL-12) gene polymorphism was found to be associated with the development of AS (94). Elevated serum IL-23 levels in AS were found in 2 pilot studies (95, 96). These data indirectly suggest the pathogenic role of IL-23 in AS. But there were also conflicting data regarding the higher susceptibility of IL-23R gene polymorphisms (97, 98) and a higher serum IL-23 level in active AS (99).
In 2011, Adamopoulos et al. (100) reported that the phenotype of the animal model with systemic overexpression of IL-23 was characterized with chronic arthritis and severe bone loss. The animal model with systemic overexpression of IL-23 was induced by hydrodynamic delivery of an IL-23 minicircle DNA into the tail veins of B10.RIII mice, and serum IL-23 was stably expressed for at least 90 days. Histological analysis of the inflamed paws and knees revealed synovitis, pronounced neovascularization/panus, myelopoiesis in the bone marrow, and extensive erosion with numerous osteoclasts. IL-23-mediated structural damage to the skeleton and extensive erosion of cortical bone were also noted by micro-CT. Compared with wild-type mice, although there were equal numbers of osteoclast precursors in bone marrow monocytes isolated from IL-23p19−/− mice, the IL-23p19−/− osteoclast precursors had impaired ability to differentiate into mature osteoclasts and had impaired ability of dentine resorption (100). In vitro, IL-23 was demonstrated to promote osteoclastogenesis in a lot of studies (56, 101–105), and IL-23 might indirectly inhibit osteoclast differentiation via activated T cells (106, 107). These findings cannot account for the pathophysiological role of IL-23 in axial SpA and did not catch enough attention. On the contrary, in 2012, the findings from another study with the same animal model satisfied our expectation (108) and rapidly attracted numerous scientists’ attention (109, 110).
In this attractive study (108), systemic overexpression of IL-23 in B10.RIII mice was also induced by hydrodynamic delivery of an IL-23 minicircle DNA into the tail veins, which resulted in long-term expression of IL-23 and elevated serum IL-23 for at least 100 days. The mice with IL-23 overexpression developed severe paw swelling. Histological analysis revealed severe entheseal inflammation, and such enthesitis was presently accompanied with new entheseal bone but no synovial joint destruction (108). The evident new bone formation in the paws of the IL-23-overexpression mice was further confirmed by high-resolution micro-CT. In the entheseal cells purified from the animal model, IL-23 promoted IL-17 and IL-22 expression. IL-22 promoted entheseal and periosteal bone formation by phosphorylation of STAT3 in osteoblasts (108). IL-23 was demonstrated to be essential and to act on RAR-related orphan receptor γt (ROR-γt)+CD3+CD4−CD8− entheseal resident T cells to induce enthesitis (108). These findings perfectly interpreted the pathophysiology of SpA to a great extent. However, the animal model with enthesitis induced by IL-23 overexpression has never been replicated by other research groups. On the contrary, later studies confirmed that the animal model with systemic overexpression of IL-23 presented peripheral arthritis with histological synovitis but no spinal inflammation or enthesitis (111). In addition, T cells are not essential for the development of enthesitis in TNFΔARE mice (deleting TNF AU-rich elements (ARE) from the mouse genome on the regulation of TNF biosynthesis) (112) and entheseal ossification in an aged DBA/1 mouse (113). Furthermore, our results demonstrated that the mRNA expression of IL-22 receptors and IL-23R was not detectable in 3 osteoblastic cell lines (i.e., C2C12, MC3T3-E1, and Saos-2 cells) and primary osteoblasts isolated from bone marrow, even after bone morphogenetic protein-2 stimulation (114). Neither IL-22 nor IL-23 showed any significant effects on primary osteoblasts, including the cell proliferation, alkaline phosphatase activity, and mRNA expression of alkaline phosphatase, osteocalcin, and Runt-related transcription factor 2 (Runx-2). The null effect of IL-23 on osteoblasts was confirmed by other research groups (107). Up to now, there are no other studies confirming the stimulatory effects of IL-22 on osteoblasts, which was reported in 2012 (108).
Taken together, there were no solid and replicable data to demonstrate that IL-23 overexpression could induce enthesitis and bone formation and that IL-22 could stimulate osteoblasts.
In Summary
The IL-23/IL-17 axis was widely accepted as an important pathway in the pathogenesis of axSpA. IL-23 was an upstream cytokine to facilitate Th17 cell expansion and then to increase IL-17 production. When good efficacy of IL-17 inhibitors has been demonstrated in axSpA, it was reasonable to expect that IL-23 inhibition would exert similar efficacy with IL-17 inhibition. Unfortunately, IL-23 inhibitors failed in the treatment of axSpA, although both IL-17 inhibitors and IL-23 inhibitors succeeded in the clinical trials of psoriasis. All the blockers of IL-6 and IL-1β, which also mediate the differentiation of Th17 cells, failed to exert satisfactory effects in axSpA either. Recently, mounting evidence shows that γδ T cells, MAIT cells, NK cells, iNKT cells, and neutrophils might produce IL-17 independently of IL-23. Furthermore, the evidence supporting IL-23 overexpression to induce enthesitis and bone formation cannot be replicated and is conflicted with the results of other research groups. Up to now, there is no solid evidence to support IL-23 is involved in the pathophysiology of axSpA.
Funding
This project was supported by a grant from the National Natural Science Foundation of China (No. 82071809).
Publisher’s Note
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Statements
Author contributions
HZ and H-LJ drafted the manuscript, and S-MD conceived the study and edited the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
DubashSBridgewoodCMcGonagleDMarzo-OrtegaH. The Advent of IL-17A Blockade in Ankylosing Spondylitis: Secukinumab, Ixekizumab and Beyond. Expert Rev Clin Immunol (2019) 15:123–34. doi: 10.1080/1744666X.2019.1561281
2
PeppleKLLinP. Targeting Interleukin-23 in the Treatment of Noninfectious Uveitis. Ophthalmology (2018) 125:1977–83. doi: 10.1016/j.ophtha.2018.05.014
3
RosineNMiceli-RichardC. Innate Cells: The Alternative Source of IL-17 in Axial and Peripheral Spondyloarthritis? Front Immunol (2020) 11:553742. doi: 10.3389/fimmu.2020.553742
4
RitchlinCAdamopoulosIE. Axial Spondyloarthritis: New Advances in Diagnosis and Management. BMJ (2021) 372:m4447. doi: 10.1136/bmj.m4447
5
BoutetMANervianiAGallo AfflittoGPitzalisC. Role of the IL-23/IL-17 Axis in Psoriasis and Psoriatic Arthritis: The Clinical Importance of Its Divergence in Skin and Joints. Int J Mol Sci (2018) 19(2):530. doi: 10.3390/ijms19020530
6
LubbertsE. The IL-23-IL-17 Axis in Inflammatory Arthritis. Nat Rev Rheumatol (2015) 11:415–29. doi: 10.1038/nrrheum.2015.53
7
BaetenDSieperJBraunJBaraliakosXDougadosMEmeryPet al. Secukinumab, an Interleukin-17a Inhibitor, in Ankylosing Spondylitis. N Engl J Med (2015) 373:2534–48. doi: 10.1056/NEJMoa1505066
8
van der HeijdeDCheng-Chung WeiJDougadosMMeasePDeodharAMaksymowychWPet al. Ixekizumab, an Interleukin-17A Antagonist in the Treatment of Ankylosing Spondylitis or Radiographic Axial Spondyloarthritis in Patients Previously Untreated With Biological Disease-Modifying Anti-Rheumatic Drugs (COAST-V): 16 Week Results of a Phase 3 Randomised, Double-Blind, Active-Controlled and Placebo-Controlled Trial. Lancet (2018) 392:2441–51. doi: 10.1016/S0140-6736(18)31946-9
9
van der HeijdeDGenslerLSDeodharABaraliakosXPoddubnyyDKivitzAet al. Dual Neutralisation of Interleukin-17A and Interleukin-17F With Bimekizumab in Patients With Active Ankylosing Spondylitis: Results From a 48-Week Phase IIb, Randomised, Double-Blind, Placebo-Controlled, Dose-Ranging Study. Ann Rheum Dis (2020) 79:595–604. doi: 10.1136/annrheumdis-2020-216980
10
ErdesSNasonovEKunderEPristromASorokaNShesternyaPet al. Primary Efficacy of Netakimab, a Novel Interleukin-17 Inhibitor, in the Treatment of Active Ankylosing Spondylitis in Adults. Clin Exp Rheumatol (2020) 38:27–34.
11
DeodharAvan der HeijdeDGenslerLSKimTHMaksymowychWPOstergaardMet al. Ixekizumab for Patients With Non-Radiographic Axial Spondyloarthritis (COAST-X): A Randomised, Placebo-Controlled Trial. Lancet (2020) 395:53–64. doi: 10.1016/S0140-6736(19)32971-X
12
DeodharABlancoRDokoupilovaEHallSKamedaHKivitzAJet al. Improvement of Signs and Symptoms of Nonradiographic Axial Spondyloarthritis in Patients Treated With Secukinumab: Primary Results of a Randomized, Placebo-Controlled Phase III Study. Arthritis Rheumatol (2021) 73:110–20. doi: 10.1002/art.41477
13
BraunJBaraliakosXDeodharAPoddubnyyDEmeryPDelichaEMet al. Secukinumab Shows Sustained Efficacy and Low Structural Progression in Ankylosing Spondylitis: 4-Year Results From the MEASURE 1 Study. Rheumatol (Oxf) (2019) 58:859–68. doi: 10.1093/rheumatology/key375
14
DeodharAGenslerLSSieperJClarkMCalderonCWangYet al. Three Multicenter, Randomized, Double-Blind, Placebo-Controlled Studies Evaluating the Efficacy and Safety of Ustekinumab in Axial Spondyloarthritis. Arthritis Rheumatol (2019) 71:258–70. doi: 10.1002/art.40728
15
BaetenDOstergaardMWeiJCSieperJJarvinenPTamLSet al. Risankizumab, an IL-23 Inhibitor, for Ankylosing Spondylitis: Results of a Randomised, Double-Blind, Placebo-Controlled, Proof-of-Concept, Dose-Finding Phase 2 Study. Ann Rheum Dis (2018) 77:1295–302. doi: 10.1136/annrheumdis-2018-213328
16
PappKABlauveltABukhaloMGooderhamMKruegerJGLacourJPet al. Risankizumab Versus Ustekinumab for Moderate-To-Severe Plaque Psoriasis. N Engl J Med (2017) 376:1551–60. doi: 10.1056/NEJMoa1607017
17
McInnesIBKavanaughAGottliebABPuigLRahmanPRitchlinCet al. Efficacy and Safety of Ustekinumab in Patients With Active Psoriatic Arthritis: 1 Year Results of the Phase 3, Multicentre, Double-Blind, Placebo-Controlled PSUMMIT 1 Trial. Lancet (2013) 382:780–9. doi: 10.1016/S0140-6736(13)60594-2
18
DeodharAHelliwellPSBoehnckeWHKollmeierAPHsiaECSubramanianRAet al. Guselkumab in Patients With Active Psoriatic Arthritis Who Were Biologic-Naive or had Previously Received TNFalpha Inhibitor Treatment (DISCOVER-1): A Double-Blind, Randomised, Placebo-Controlled Phase 3 Trial. Lancet (2020) 395:1115–25. doi: 10.1016/S0140-6736(20)30265-8
19
HasegawaHMizoguchiIChibaYOhashiMXuMYoshimotoT. Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family. Front Immunol (2016) 7:479. doi: 10.3389/fimmu.2016.00479
20
van TokMNNaSLaoCRAlviMPotsDvan de SandeMGHet al. The Initiation, But Not the Persistence, of Experimental Spondyloarthritis Is Dependent on Interleukin-23 Signaling. Front Immunol (2018) 9:1550. doi: 10.3389/fimmu.2018.01550
21
MandourMChenSvan de SandeMGH. The Role of the IL-23/IL-17 Axis in Disease Initiation in Spondyloarthritis: Lessons Learned From Animal Models. Front Immunol (2021) 12:618581. doi: 10.3389/fimmu.2021.618581
22
McGonagleDWatadASharifKBridgewoodC. Why Inhibition of IL-23 Lacked Efficacy in Ankylosing Spondylitis. Front Immunol (2021) 12:614255. doi: 10.3389/fimmu.2021.614255
23
SiebertSMcGuckenAMcInnesIB. The IL-23/IL-17A Axis in Spondyloarthritis: Therapeutics Informing Pathogenesis? Curr Opin Rheumatol (2020) 32:349–56. doi: 10.1097/BOR.0000000000000719
24
van TokMNvan DuivenvoordeLMKramerIIngoldPPfisterSRothLet al. Interleukin-17a Inhibition Diminishes Inflammation and New Bone Formation in Experimental Spondyloarthritis. Arthritis Rheumatol (2019) 71:612–25. doi: 10.1002/art.40770
25
MurphyCALangrishCLChenYBlumenscheinWMcClanahanTKasteleinRAet al. Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation. J Exp Med (2003) 198:1951–7. doi: 10.1084/jem.20030896
26
CornelissenFAsmawidjajaPSMusAMCornethOKiklyKLubbertsE. IL-23 Dependent and Independent Stages of Experimental Arthritis: No Clinical Effect of Therapeutic IL-23p19 Inhibition in Collagen-Induced Arthritis. PloS One (2013) 8:e57553. doi: 10.1371/journal.pone.0057553
27
CornelissenFMusAMAsmawidjajaPSvan HamburgJPTockerJLubbertsE. Interleukin-23 Is Critical for Full-Blown Expression of a non-Autoimmune Destructive Arthritis and Regulates Interleukin-17A and RORgammat in Gammadelta T Cells. Arthritis Res Ther (2009) 11:R194. doi: 10.1186/ar2893
28
YagoTNankeYKawamotoMFuruyaTKobashigawaTKamataniNet al. IL-23 Induces Human Osteoclastogenesis via IL-17 In Vitro, and Anti-IL-23 Antibody Attenuates Collagen-Induced Arthritis in Rats. Arthritis Res Ther (2007) 9:R96. doi: 10.1186/ar2297
29
XuzhuGKomai-KomaMLeungBPHoweHSMcSharryCMcInnesIBet al. Resveratrol Modulates Murine Collagen-Induced Arthritis by Inhibiting Th17 and B-Cell Function. Ann Rheum Dis (2012) 71:129–35. doi: 10.1136/ard.2011.149831
30
OlsonMVLiuYCDangiBPaul ZimmerJSalemNJrNaurothJM. Docosahexaenoic Acid Reduces Inflammation and Joint Destruction in Mice With Collagen-Induced Arthritis. Inflamm Res (2013) 62:1003–13. doi: 10.1007/s00011-013-0658-4
31
YoshimuraSAsanoKNakaneA. Attenuation of Collagen-Induced Arthritis in Mice by Salmon Proteoglycan. BioMed Res Int (2014) 2014:406453. doi: 10.1155/2014/406453
32
TakahashiYTanakaMMuraiRKuribayashiKKobayashiDYanagiharaNet al. Prophylactic and Therapeutic Effects of Acanthopanax Senticosus Harms Extract on Murine Collagen-Induced Arthritis. Phytother Res (2014) 28:1513–9. doi: 10.1002/ptr.5157
33
TuYWangKLiangYJiaXWangLWanJBet al. Glycine Tabacina Ethanol Extract Ameliorates Collagen-Induced Arthritis in Rats via Inhibiting Pro-Inflammatory Cytokines and Oxidation. J Ethnopharmacol (2019) 237:20–7. doi: 10.1016/j.jep.2019.03.035
34
KoraniMJamshidiM. The Effect of Aqueous Extract of Trachyspermum Ammi Seeds and Ibuprofen on Inflammatory Gene Expression in the Cartilage Tissue of Rats With Collagen-Induced Arthritis. J Inflamm Res (2020) 13:133–9. doi: 10.2147/JIR.S236242
35
InoueKMotonagaASuzukaHYoshifusaHFujisawaHNishimuraTet al. Effect of Etodolac on Type-II Collagen-Induced Arthritis in Mice. Agents Actions (1993) 39:187–94. doi: 10.1007/BF01998973
36
TsuboiHNampeiAMatsuiYHashimotoJKawaiSOchiTet al. Celecoxib Prevents Juxta-Articular Osteopenia and Growth Plate Destruction Adjacent to Inflamed Joints in Rats With Collagen-Induced Arthritis. Mod Rheumatol (2007) 17:115–22. doi: 10.1007/s10165-007-0552-4
37
MouldAWScotneyPGrecoSAHaywardNKNashAKayGFet al. Prophylactic But Not Therapeutic Activity of a Monoclonal Antibody That Neutralizes the Binding of VEGF-B to VEGFR-1 in a Murine Collagen-Induced Arthritis Model. Rheumatol (Oxf) (2008) 47:263–6. doi: 10.1093/rheumatology/kem369
38
MiotlaJMaciewiczRKendrewJFeldmannMPaleologE. Treatment With Soluble VEGF Receptor Reduces Disease Severity in Murine Collagen-Induced Arthritis. Lab Invest (2000) 80:1195–205. doi: 10.1038/labinvest.3780127
39
FavaRAOlsenNJSpencer-GreenGYeoKTYeoTKBerseBet al. Vascular Permeability Factor/Endothelial Growth Factor (VPF/VEGF): Accumulation and Expression in Human Synovial Fluids and Rheumatoid Synovial Tissue. J Exp Med (1994) 180:341–6. doi: 10.1084/jem.180.1.341
40
HegenMKeithJCJrCollinsMNickerson-NutterCL. Utility of Animal Models for Identification of Potential Therapeutics for Rheumatoid Arthritis. Ann Rheum Dis (2008) 67:1505–15. doi: 10.1136/ard.2007.076430
41
NakaeSNambuASudoKIwakuraY. Suppression of Immune Induction of Collagen-Induced Arthritis in IL-17-Deficient Mice. J Immunol (2003) 171:6173–7. doi: 10.4049/jimmunol.171.11.6173
42
KoendersMIKollsJKOppers-WalgreenBvan den BersselaarLJoostenLASchurrJRet al. Interleukin-17 Receptor Deficiency Results in Impaired Synovial Expression of Interleukin-1 and Matrix Metalloproteinases 3, 9, and 13 and Prevents Cartilage Destruction During Chronic Reactivated Streptococcal Cell Wall-Induced Arthritis. Arthritis Rheum (2005) 52:3239–47. doi: 10.1002/art.21342
43
AdamopoulosIESuzukiEChaoCCGormanDAddaSMaverakisEet al. IL-17A Gene Transfer Induces Bone Loss and Epidermal Hyperplasia Associated With Psoriatic Arthritis. Ann Rheum Dis (2015) 74:1284–92. doi: 10.1136/annrheumdis-2013-204782
44
BushKAFarmerKMWalkerJSKirkhamBW. Reduction of Joint Inflammation and Bone Erosion in Rat Adjuvant Arthritis by Treatment With Interleukin-17 Receptor IgG1 Fc Fusion Protein. Arthritis Rheum (2002) 46:802–5. doi: 10.1002/art.10173
45
LubbertsEKoendersMIOppers-WalgreenBvan den BersselaarLCoenen-de RooCJJoostenLAet al. Treatment With a Neutralizing Anti-Murine Interleukin-17 Antibody After the Onset of Collagen-Induced Arthritis Reduces Joint Inflammation, Cartilage Destruction, and Bone Erosion. Arthritis Rheum (2004) 50:650–9. doi: 10.1002/art.20001
46
RohnTAJenningsGTHernandezMGrestPBeckMZouYet al. Vaccination Against IL-17 Suppresses Autoimmune Arthritis and Encephalomyelitis. Eur J Immunol (2006) 36:2857–67. doi: 10.1002/eji.200636658
47
KelchtermansHSchurgersEGeboesLMiteraTVan DammeJVan SnickJet al. Effector Mechanisms of Interleukin-17 in Collagen-Induced Arthritis in the Absence of Interferon-Gamma and Counteraction by Interferon-Gamma. Arthritis Res Ther (2009) 11:R122. doi: 10.1186/ar2787
48
GenoveseMCDurezPRichardsHBSupronikJDokoupilovaEMazurovVet al. Efficacy and Safety of Secukinumab in Patients With Rheumatoid Arthritis: A Phase II, Dose-Finding, Double-Blind, Randomised, Placebo Controlled Study. Ann Rheum Dis (2013) 72:863–9. doi: 10.1136/annrheumdis-2012-201601
49
GenoveseMCGreenwaldMChoCSBermanAJinLCameronGSet al. A Phase II Randomized Study of Subcutaneous Ixekizumab, an Anti-Interleukin-17 Monoclonal Antibody, in Rheumatoid Arthritis Patients Who Were Naive to Biologic Agents or had an Inadequate Response to Tumor Necrosis Factor Inhibitors. Arthritis Rheumatol (2014) 66:1693–704. doi: 10.1002/art.38617
50
PavelkaKChonYNewmarkRLinSLBaumgartnerSEronduN. A Study to Evaluate the Safety, Tolerability, and Efficacy of Brodalumab in Subjects With Rheumatoid Arthritis and an Inadequate Response to Methotrexate. J Rheumatol (2015) 42:912–9. doi: 10.3899/jrheum.141271
51
TlustochowiczWRahmanPSerioloBKrammerGPorterBWidmerAet al. Efficacy and Safety of Subcutaneous and Intravenous Loading Dose Regimens of Secukinumab in Patients With Active Rheumatoid Arthritis: Results From a Randomized Phase II Study. J Rheumatol (2016) 43:495–503. doi: 10.3899/jrheum.150117
52
HarringtonLEHattonRDManganPRTurnerHMurphyTLMurphyKMet al. Interleukin 17-Producing CD4+ Effector T Cells Develop via a Lineage Distinct From the T Helper Type 1 and 2 Lineages. Nat Immunol (2005) 6:1123–32. doi: 10.1038/ni1254
53
ParkHLiZYangXOChangSHNurievaRWangYHet al. A Distinct Lineage of CD4 T Cells Regulates Tissue Inflammation by Producing Interleukin 17. Nat Immunol (2005) 6:1133–41. doi: 10.1038/ni1261
54
AggarwalSGhilardiNXieMHde SauvageFJGurneyAL. Interleukin-23 Promotes a Distinct CD4 T Cell Activation State Characterized by the Production of Interleukin-17. J Biol Chem (2003) 278:1910–4. doi: 10.1074/jbc.M207577200
55
LangrishCLChenYBlumenscheinWMMattsonJBashamBSedgwickJDet al. IL-23 Drives a Pathogenic T Cell Population That Induces Autoimmune Inflammation. J Exp Med (2005) 201:233–40. doi: 10.1084/jem.20041257
56
VeldhoenMHockingRJAtkinsCJLocksleyRMStockingerB. TGFbeta in the Context of an Inflammatory Cytokine Milieu Supports De Novo Differentiation of IL-17-Producing T Cells. Immunity (2006) 24:179–89. doi: 10.1016/j.immuni.2006.01.001
57
Acosta-RodriguezEVNapolitaniGLanzavecchiaASallustoF. Interleukins 1beta and 6 But Not Transforming Growth Factor-Beta Are Essential for the Differentiation of Interleukin 17-Producing Human T Helper Cells. Nat Immunol (2007) 8:942–9. doi: 10.1038/ni1496
58
HemdanNYBirkenmeierGWichmannG. Key Molecules in the Differentiation and Commitment Program of T Helper 17 (Th17) Cells Up-to-Date. Immunol Lett (2012) 148:97–109. doi: 10.1016/j.imlet.2012.09.007
59
Layh-SchmittGColbertRA. The Interleukin-23/Interleukin-17 Axis in Spondyloarthritis. Curr Opin Rheumatol (2008) 20:392–7. doi: 10.1097/BOR.0b013e328303204b
60
International Genetics of Ankylosing Spondylitis, CCortesAHadlerJPointonJPRobinsonPCKaraderiTet al. Identification of Multiple Risk Variants for Ankylosing Spondylitis Through High-Density Genotyping of Immune-Related Loci. Nat Genet (2013) 45:730–8. doi: 10.1038/ng.2667
61
LiZBrownMA. Progress of Genome-Wide Association Studies of Ankylosing Spondylitis. Clin Transl Immunol (2017) 6:e163. doi: 10.1038/cti.2017.49
62
JandusCBioleyGRivalsJPDudlerJSpeiserDRomeroP. Increased Numbers of Circulating Polyfunctional Th17 Memory Cells in Patients With Seronegative Spondylarthritides. Arthritis Rheum (2008) 58:2307–17. doi: 10.1002/art.23655
63
ShenHGoodallJCHill GastonJS. Frequency and Phenotype of Peripheral Blood Th17 Cells in Ankylosing Spondylitis and Rheumatoid Arthritis. Arthritis Rheum (2009) 60:1647–56. doi: 10.1002/art.24568
64
Di MeglioPDi CesareALaggnerUChuCCNapolitanoLVillanovaFet al. The IL23R R381Q Gene Variant Protects Against Immune-Mediated Diseases by Impairing IL-23-Induced Th17 Effector Response in Humans. PloS One (2011) 6:e17160. doi: 10.1371/journal.pone.0017160
65
SarinRWuXAbrahamC. Inflammatory Disease Protective R381Q IL23 Receptor Polymorphism Results in Decreased Primary CD4+ and CD8+ Human T-Cell Functional Responses. Proc Natl Acad Sci USA (2011) 108:9560–5. doi: 10.1073/pnas.1017854108
66
LekpaFKPoulainCWendlingDSoubrierMDe BandtMBerthelotJMet al. Is IL-6 an Appropriate Target to Treat Spondyloarthritis Patients Refractory to Anti-TNF Therapy? A Multicentre Retrospective Observational Study. Arthritis Res Ther (2012) 14:R53. doi: 10.1186/ar3766
67
SieperJBraunJKayJBadalamentiSRadinARJiaoLet al. Sarilumab for the Treatment of Ankylosing Spondylitis: Results of a Phase II, Randomised, Double-Blind, Placebo-Controlled Study (ALIGN). Ann Rheum Dis (2015) 74:1051–7. doi: 10.1136/annrheumdis-2013-204963
68
HaibelHRudwaleitMListingJSieperJ. Open Label Trial of Anakinra in Active Ankylosing Spondylitis Over 24 Weeks. Ann Rheum Dis (2005) 64:296–8. doi: 10.1136/ard.2004.023176
69
TaamsLSSteelKJASrenathanUBurnsLAKirkhamBW. IL-17 in the Immunopathogenesis of Spondyloarthritis. Nat Rev Rheumatol (2018) 14:453–66. doi: 10.1038/s41584-018-0044-2
70
WendlingDCedozJPRacadotEDumoulinG. Serum IL-17, BMP-7, and Bone Turnover Markers in Patients With Ankylosing Spondylitis. Joint Bone Spine (2007) 74:304–5. doi: 10.1016/j.jbspin.2006.11.005
71
AppelHMaierRWuPScheerRHempfingAKayserRet al. Analysis of IL-17(+) Cells in Facet Joints of Patients With Spondyloarthritis Suggests That the Innate Immune Pathway Might be of Greater Relevance Than the Th17-Mediated Adaptive Immune Response. Arthritis Res Ther (2011) 13:R95. doi: 10.1186/ar3370
72
OrtegaCFernandezASCarrilloJMRomeroPMolinaIJMorenoJCet al. IL-17-Producing CD8+ T Lymphocytes From Psoriasis Skin Plaques Are Cytotoxic Effector Cells That Secrete Th17-Related Cytokines. J Leukoc Biol (2009) 86:435–43. doi: 10.1189/JLB.0109046
73
MartinBHirotaKCuaDJStockingerBVeldhoenM. Interleukin-17-Producing Gammadelta T Cells Selectively Expand in Response to Pathogen Products and Environmental Signals. Immunity (2009) 31:321–30. doi: 10.1016/j.immuni.2009.06.020
74
DusseauxMMartinESerriariNPeguilletIPremelVLouisDet al. Human MAIT Cells are Xenobiotic-Resistant, Tissue-Targeted, CD161hi IL-17-Secreting T Cells. Blood (2011) 117:1250–9. doi: 10.1182/blood-2010-08-303339
75
CellaMFuchsAVermiWFacchettiFOteroKLennerzJKet al. A Human Natural Killer Cell Subset Provides an Innate Source of IL-22 for Mucosal Immunity. Nature (2009) 457:722–5. doi: 10.1038/nature07537
76
PassosSTSilverJSO'HaraACSehyDStumhoferJSHunterCA. IL-6 Promotes NK Cell Production of IL-17 During Toxoplasmosis. J Immunol (2010) 184:1776–83. doi: 10.4049/jimmunol.0901843
77
MichelMLKellerACPagetCFujioMTrotteinFSavagePBet al. Identification of an IL-17-Producing NK1.1(neg) iNKT Cell Population Involved in Airway Neutrophilia. J Exp Med (2007) 204:995–1001. doi: 10.1084/jem.20061551
78
BuonocoreSAhernPPUhligHHIvanovIILittmanDRMaloyKJet al. Innate Lymphoid Cells Drive Interleukin-23-Dependent Innate Intestinal Pathology. Nature (2010) 464:1371–5. doi: 10.1038/nature08949
79
CrellinNKTrifariSKaplanCDCupedoTSpitsH. Human NKp44+IL-22+ Cells and LTi-Like Cells Constitute a Stable RORC+ Lineage Distinct From Conventional Natural Killer Cells. J Exp Med (2010) 207:281–90. doi: 10.1084/jem.20091509
80
TakatoriHKannoYWatfordWTTatoCMWeissGIvanovIIet al. Lymphoid Tissue Inducer-Like Cells Are an Innate Source of IL-17 and IL-22. J Exp Med (2009) 206:35–41. doi: 10.1084/jem.20072713
81
LiLHuangLVergisALYeHBajwaANarayanVet al. IL-17 Produced by Neutrophils Regulates IFN-Gamma-Mediated Neutrophil Migration in Mouse Kidney Ischemia-Reperfusion Injury. J Clin Invest (2010) 120:331–42. doi: 10.1172/JCI38702
82
VenkenKJacquesPMortierCLabadiaMEDecruyTCoudenysJet al. RORgammat Inhibition Selectively Targets IL-17 Producing iNKT and Gammadelta-T Cells Enriched in Spondyloarthritis Patients. Nat Commun (2019) 10:9. doi: 10.1038/s41467-018-07911-6
83
GraceyEQaiyumZAlmaghlouthILawsonDKarkiSAvvaruNet al. IL-7 Primes IL-17 in Mucosal-Associated Invariant T (MAIT) Cells, Which Contribute to the Th17-Axis in Ankylosing Spondylitis. Ann Rheum Dis (2016) 75:2124–32. doi: 10.1136/annrheumdis-2015-208902
84
HayashiEChibaATadaKHagaKKitagaichiMNakajimaSet al. Involvement of Mucosal-Associated Invariant T Cells in Ankylosing Spondylitis. J Rheumatol (2016) 43:1695–703. doi: 10.3899/jrheum.151133
85
ToussirotELaheurteCGauglerBGabrielDSaasP. Increased IL-22- and IL-17a-Producing Mucosal-Associated Invariant T Cells in the Peripheral Blood of Patients With Ankylosing Spondylitis. Front Immunol (2018) 9:1610. doi: 10.3389/fimmu.2018.01610
86
CuthbertRJWatadAFragkakisEMDunsmuirRLoughenburyPKhanAet al. Evidence That Tissue Resident Human Enthesis gammadeltaT-Cells can Produce IL-17A Independently of IL-23R Transcript Expression. Ann Rheum Dis (2019) 78:1559–65. doi: 10.1136/annrheumdis-2019-215210
87
CicciaFGugginoGRizzoASaievaLPeraltaSGiardinaAet al. Type 3 Innate Lymphoid Cells Producing IL-17 and IL-22 Are Expanded in the Gut, in the Peripheral Blood, Synovial Fluid and Bone Marrow of Patients With Ankylosing Spondylitis. Ann Rheum Dis (2015) 74:1739–47. doi: 10.1136/annrheumdis-2014-206323
88
TriggianesePConigliaroPChimentiMSBianconeLMonteleoneGPerriconeRet al. Evidence of IL-17 Producing Innate Lymphoid Cells in Peripheral Blood From Patients With Enteropathic Spondyloarthritis. Clin Exp Rheumatol (2016) 34:1085–93. doi: 10.26226/morressier.56e174d1d462b8028d88a66b
89
ChowdhuryACChaurasiaSMishraSKAggarwalAMisraR. IL-17 and IFN-Gamma Producing NK and Gammadelta-T Cells are Preferentially Expanded in Synovial Fluid of Patients With Reactive Arthritis and Undifferentiated Spondyloarthritis. Clin Immunol (2017) 183:207–12. doi: 10.1016/j.clim.2017.03.016
90
LeeJSTatoCMJoyce-ShaikhBGulenMFCayatteCChenYet al. Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability. Immunity (2015) 43:727–38. doi: 10.1016/j.immuni.2015.09.003
91
BridgewoodCWatadARussellTPalmerTMMarzo-OrtegaHKhanAet al. Identification of Myeloid Cells in the Human Enthesis as the Main Source of Local IL-23 Production. Ann Rheum Dis (2019) 78:929–33. doi: 10.1136/annrheumdis-2018-214944
92
AppelHMaierRBleilJHempfingALoddenkemperCSchlichtingUet al. In Situ Analysis of Interleukin-23- and Interleukin-12-Positive Cells in the Spine of Patients With Ankylosing Spondylitis. Arthritis Rheum (2013) 65:1522–9. doi: 10.1002/art.37937
93
Wellcome Trust Case Control, CAustralo-Anglo-American Spondylitis, CBurtonPRClaytonDGCardonLRCraddockNet al. Association Scan of 14,500 Nonsynonymous SNPs in Four Diseases Identifies Autoimmunity Variants. Nat Genet (2007) 39:1329–37. doi: 10.1038/ng.2007.17
94
WongRHWeiJCHuangCHLeeHSChiouSYLinSHet al. Association of IL-12B Genetic Polymorphism With the Susceptibility and Disease Severity of Ankylosing Spondylitis. J Rheumatol (2012) 39:135–40. doi: 10.3899/jrheum.110613
95
MeiYPanFGaoJGeRDuanZZengZet al. Increased Serum IL-17 and IL-23 in the Patient With Ankylosing Spondylitis. Clin Rheumatol (2011) 30:269–73. doi: 10.1007/s10067-010-1647-4
96
UgurMBaygutalpNKMelikogluMABaygutalpFAltasEUSeferogluB. Elevated Serum Interleukin-23 Levels in Ankylosing Spondylitis Patients and the Relationship With Disease Activity. Nagoya J Med Sci (2015) 77:621–7.
97
QianBPJiangJJiMLWangBYuYQiuY. Lack of Associations Between Two Previously Identified Susceptible Single Nucleotide Polymorphisms of Interleukin-23 Receptor Gene and Ankylosing Spondylitis: A Replication Study in a Chinese Han Population. BMC Musculoskelet Disord (2013) 14:190. doi: 10.1186/1471-2474-14-190
98
DavidsonSIWuXLiuYWeiMDanoyPAThomasGet al. Association of ERAP1, But Not IL23R, With Ankylosing Spondylitis in a Han Chinese Population. Arthritis Rheum (2009) 60:3263–8. doi: 10.1002/art.24933
99
DeveciHCagliyan TurkAOzmenZCDeveciK. Serum Interleukin-23/17 Levels in Ankylosing Spondylitis Patients Treated With Nonsteroidal Anti-Inflammatory Drugs: A Prospective Cohort Study. J Interferon Cytokine Res (2019) 39:572–6. doi: 10.1089/jir.2019.0052
100
AdamopoulosIETessmerMChaoCCAddaSGormanDPetroMet al. IL-23 is Critical for Induction of Arthritis, Osteoclast Formation, and Maintenance of Bone Mass. J Immunol (2011) 187:951–9. doi: 10.4049/jimmunol.1003986
101
ChenLWeiXQEvansBJiangWAeschlimannD. IL-23 Promotes Osteoclast Formation by Up-Regulation of Receptor Activator of NF-kappaB (RANK) Expression in Myeloid Precursor Cells. Eur J Immunol (2008) 38:2845–54. doi: 10.1002/eji.200838192
102
JuJHChoMLMoonYMOhHJParkJSJhunJYet al. IL-23 Induces Receptor Activator of NF-kappaB Ligand Expression on CD4+ T Cells and Promotes Osteoclastogenesis in an Autoimmune Arthritis Model. J Immunol (2008) 181:1507–18. doi: 10.4049/jimmunol.181.2.1507
103
KangYKZhangMC. IL-23 Promotes Osteoclastogenesis in Osteoblast-Osteoclast Co-Culture System. Genet Mol Res (2014) 13:4673–9. doi: 10.4238/2014.June.18.10
104
ShinHSSarinRDixitNWuJGershwinEBowmanEPet al. Crosstalk Among IL-23 and DNAX Activating Protein of 12 kDa-Dependent Pathways Promotes Osteoclastogenesis. J Immunol (2015) 194:316–24. doi: 10.4049/jimmunol.1401013
105
BouchareychasLGrossingerEMKangMQiuHAdamopoulosIE. Critical Role of LTB4/BLT1 in IL-23-Induced Synovial Inflammation and Osteoclastogenesis. Via NF-kappaB J Immunol (2017) 198:452–60. doi: 10.4049/jimmunol.1601346
106
QuinnJMSimsNASalehHMirosaDThompsonKBouralexisSet al. IL-23 Inhibits Osteoclastogenesis Indirectly Through Lymphocytes and is Required for the Maintenance of Bone Mass in Mice. J Immunol (2008) 181:5720–9. doi: 10.4049/jimmunol.181.8.5720
107
KamiyaSNakamuraCFukawaTOnoKOhwakiTYoshimotoTet al. Effects of IL-23 and IL-27 on Osteoblasts and Osteoclasts: Inhibitory Effects on Osteoclast Differentiation. J Bone Miner Metab (2007) 25:277–85. doi: 10.1007/s00774-007-0766-8
108
SherlockJPJoyce-ShaikhBTurnerSPChaoCCSatheMGreinJet al. IL-23 Induces Spondyloarthropathy by Acting on ROR-Gammat+ CD3+CD4-CD8- Entheseal Resident T Cells. Nat Med (2012) 18:1069–76. doi: 10.1038/nm.2817
109
LoriesRJMcInnesIB. Primed for Inflammation: Enthesis-Resident T Cells. Nat Med (2012) 18:1018–9. doi: 10.1038/nm.2854
110
RayK. Inflammation: IL-23 Tees Off Enthesitis. Nat Rev Immunol (2012) 12:552–3. doi: 10.1038/nri3269
111
HaleyEKMatmusaevMHossainINDavinSMartinTMErmannJ. The Impact of Genetic Background and Sex on the Phenotype of IL-23 Induced Murine Spondyloarthritis. PloS One (2021) 16:e0247149. doi: 10.1371/journal.pone.0247149
112
JacquesPLambrechtSVerheugenEPauwelsEKolliasGArmakaMet al. Proof of Concept: Enthesitis and New Bone Formation in Spondyloarthritis are Driven by Mechanical Strain and Stromal Cells. Ann Rheum Dis (2014) 73:437–45. doi: 10.1136/annrheumdis-2013-203643
113
CorthayAHanssonASHolmdahlR. T Lymphocytes are Not Required for the Spontaneous Development of Entheseal Ossification Leading to Marginal Ankylosis in the DBA/1 Mouse. Arthritis Rheum (2000) 43:844–51. doi: 10.1002/1529-0131(200004)43:4<844::AID-ANR15>3.0.CO;2-B
114
ZhangJRPangDDTongQLiuXSuDFDaiSM. Different Modulatory Effects of IL-17, IL-22, and IL-23 on Osteoblast Differentiation. Mediators Inflamm (2017) 2017:5950395. doi: 10.1155/2017/5950395
Summary
Keywords
axial spondyloarthritis, IL-23, Th17 cells, IL-17, IL-23 inhibitors, ankylosing spondylitis
Citation
Zhang H, Jiang H-L and Dai S-M (2022) No Significant Effects of IL-23 on Initiating and Perpetuating the Axial Spondyloarthritis: The Reasons for the Failure of IL-23 Inhibitors. Front. Immunol. 13:818413. doi: 10.3389/fimmu.2022.818413
Received
19 November 2021
Accepted
19 January 2022
Published
10 February 2022
Volume
13 - 2022
Edited by
Mi-La Cho, Catholic University of Korea, South Korea
Reviewed by
Iannis Adamopoulos, Beth Israel Deaconess Medical Center and Harvard Medical School, United States; Hong Ki Min, Konkuk University Medical Center, South Korea
Updates
Copyright
© 2022 Zhang, Jiang and Dai.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Sheng-Ming Dai, shengmingdai@163.com
This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology
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