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The complex crosstalk between the immune and the skeletal systems plays an indispensable role in the maintenance of skeletal homeostasis. Various cytokines are involved, including interleukin (IL)-17A. A variety of immune and inflammatory cells produces IL-17A, especially Th17 cells, a subtype of CD4 + T cells. IL-17A orchestrates diverse inflammatory and immune processes. IL-17A induces direct and indirect effects on osteoclasts. The dual role of IL-17A on osteoclasts partly depends on its concentrations and interactions with other factors. Interestingly, IL-17A exerts a dual role in osteoblasts in vitro . IL-17A is a bone-destroying cytokine in numerous immune-mediated bone diseases including postmenopausal osteoporosis (PMOP), rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondylarthritis (axSpA). This review will summarize and discuss the pathophysiological roles of IL-17A on the skeletal system and its potential strategies for application in immune-mediated bone diseases.

Silicosis is a global occupational disease characterized by lung dysfunction, pulmonary inflammation, and fibrosis, for which there is a lack of effective drugs. Pirfenidone has been shown to exert anti-inflammatory and anti-fibrotic properties in the lung. However, whether and how pirfenidone is effective against silicosis remains unknown. Here, we evaluated the efficacy of pirfenidone in the treatment of early and advanced silicosis in an experimental mouse model and explored its potential pharmacological mechanisms. We found that pirfenidone alleviated silica-induced lung dysfunction, secretion of inflammatory cytokines (TNF-α, IL-1β, IL-6) and deposition of fibrotic proteins (collagen I and fibronectin) in both early and advanced silicosis models. Moreover, we observed that both 100 and 200 mg/kg pirfenidone can effectively treat early-stage silicosis, while 400 mg/kg was recommended for advanced silicosis. Mechanistically, antibody array and bioinformatic analysis showed that the pathways related to IL-17 secretion, including JAK-STAT pathway, Th17 differentiation, and IL-17 pathway, might be involved in the treatment of silicosis by pirfenidone. Further in vivo experiments confirmed that pirfenidone reduced the production of IL-17A induced by silica exposure via inhibiting STAT3 phosphorylation. Neutralizing IL-17A by anti-IL-17A antibody improved lung function and reduced pulmonary inflammation and fibrosis in silicosis animals. Collectively, our study has demonstrated that pirfenidone effectively ameliorated silica-induced lung dysfunction, pulmonary inflammation and fibrosis in mouse models by inhibiting the secretion of IL-17A.

Periodontitis is a chronic immunoinflammatory disease involving various components that affect the tissues surrounding the tooth. The host immune response to the presence of periodontopathogenic microorganisms activates several cytokine systems involved in alveolar bone resorption in periodontitis; among them is the receptor activator of nuclear factor-κB (RANK)/receptor activator of nuclear factor-κB ligand (RANKL) system, which depends on the interleukin (IL)-23/IL-17 axis. There is a tendency toward increased IL-23, IL-17, and IL-17 receptor (IL-17RA) and a discrepancy in IL-23 receptor (IL-23R) in gingival tissue (GT) of patients with periodontitis. Therefore, the aim of this study was to quantify the expression of the IL-23/IL-17A axis using the western blotting (WB) technique in GT samples from patients with periodontitis. This cross-sectional study included 49 subjects: 25 healthy subjects and 24 subjects with periodontitis. GT samples were collected during periodontal surgery. WB was used to evaluate the levels of IL-23, IL-17A, IL-23R, and IL-17RA. We found a significant increase in IL-23, IL-17A, IL-23R, and IL-17RA protein levels in the periodontitis group compared with the healthy group; we also detected bands with unexpected molecular weights for both receptors. Moreover, we found a significant positive correlation between IL-23 and IL-17A with both receptors, while IL-23, IL-17A, IL-23R, and IL-17RA correlated positively with two periodontal clinical parameters, namely the clinical attachment level and the percentage of radiographic bone loss (%RBL). In this study, we detected overexpression of IL-23, IL-17A, and their receptors in GT of patients with periodontitis, confirming that the IL-23/IL-17A axis is involved in periodontal disease.

The neurological injury and repair mechanisms after ischemic stroke are complex. The inflammatory response is present throughout stroke onset and functional recovery, in which CD4 + T helper(Th) cells play a non-negligible role. Th17 cells, differentiated from CD4 + Th cells, are regulated by various extracellular signals, transcription factors, RNA, and post-translational modifications. Th17 cells specifically produce interleukin-17A(IL-17A), which has been reported to have pro-inflammatory effects in many studies. Recently, experimental researches showed that Th17 cells and IL-17A play an important role in promoting stroke pathogenesis (atherosclerosis), inducing secondary damage after stroke, and regulating post-stroke repair. This makes Th17 and IL-17A a possible target for the treatment of stroke. In this paper, we review the mechanism of action of Th17 cells and IL-17A in ischemic stroke and the progress of research on targeted therapy.

Background The study aimed to assess 52-week efficacy and safety of secukinumab self-administration by autoinjector in patients with active psoriatic arthritis (PsA) in the FUTURE 3 study ( ClinicalTrials.gov NCT01989468). Methods Patients (≥ 18 years of age; N = 414) with active PsA were randomized 1:1:1 to subcutaneous (s.c.) secukinumab 300 mg, 150 mg, or placebo at baseline, weeks 1, 2, 3, and 4, and every 4 weeks thereafter. Per clinical response, placebo-treated patients were re-randomized to s.c. secukinumab 300 or 150 mg at week 16 (nonresponders) or week 24 (responders) and stratified at randomization by prior anti-tumor necrosis factor (TNF) therapy (anti-TNF-naïve, 68.1%; intolerant/inadequate response (anti-TNF-IR), 31.9%). The primary endpoint was the proportion of patients achieving at least 20% improvement in American College of Rheumatology response criteria (ACR20) at week 24. Autoinjector usability was evaluated by Self-Injection Assessment Questionnaire (SIAQ). Results Overall, 92.1% (300 mg), 91.3% (150 mg), and 93.4% (placebo) of patients completed 24 weeks, and 84.9% (300 mg) and 79.7% (150 mg) completed 52 weeks. In the overall population (combined anti-TNF-naïve and anti-TNF-IR), ACR20 response rate at week 24 was significantly higher in secukinumab groups (300 mg, 48.2% ( p < 0.0001); 150 mg, 42% ( p < 0.0001); placebo, 16.1%) and was sustained through 52 weeks. SIAQ results showed that more than 93% of patients were satisfied/very satisfied with autoinjector usage. Secukinumab was well tolerated with no new or unexpected safety signals reported. Conclusions Secukinumab provided sustained improvements in signs and symptoms in active PsA patients through 52 weeks. High acceptability of autoinjector was observed. The safety profile was consistent with that reported previously. Trial registration ClinicalTrials.gov NCT01989468 . Registered 21 November 2013. EudraCT 2013–004002-25 . Registered 17 December 2013.

Endometriosis is a debilitating gynecological disease characterized by the extrauterine presence of endometrial-like tissues located on the peritoneal membrane and organs of the pelvic cavity. Notably, dysfunctional immune activation in women with endometriosis could also contribute to the development of disease. In particular, alternatively activated (M2) peritoneal macrophages are shown to aid peritoneal lesion development by promoting remodeling of extracellular matrix and neovascularization of lesions. However, the stimuli responsible for polarizing M2 macrophages in endometriosis remain elusive. Interleukin-17A (IL-17A) can induce M2 macrophage polarization in other disease models and IL-17A is elevated in the plasma and endometriotic lesions of women with endometriosis. In this study, we investigated whether IL-17A could induce macrophage recruitment and M2 polarization, while promoting endometriotic lesion growth through enhanced vascularization. By utilizing a co-culture of macrophage-like THP-1 cells with an endometriotic epithelial cell line, our results suggest that IL-17A indirectly induces M2 markers CCL17 and CD206 by interacting with endometriotic epithelial cells. Further, in a syngeneic mouse model of endometriosis, IL-17A treatment increased macrophages in the peritoneum, which were also M2 in phenotype. However, IL-17A treatment did not augment proliferation or vascularization of the lesion in the study time frame. These findings suggest that IL-17A may be a stimulus inducing the pathogenic polarization of macrophages into the M2 phenotype by first acting on the endometriotic lesion itself.

Background: The incidence rate of uveitis in secukinumab-treated patients with axial spondyloarthritis (axSpA) was previously reported. Objective: To evaluate the incidence rate of uveitis in patients with axSpA and psoriatic arthritis (PsA) treated with secukinumab or placebo during placebo-controlled phase III studies. Design: This was a post hoc analysis from 11 phase III studies. Methods: Pooled data from axSpA (MEASURE 1–5 and PREVENT studies) and PsA (FUTURE 1–5 studies) were analyzed. Results: In the axSpA cohort (N = 1980), the incidence rate for uveitis was 1.29 per 100 patient-years in the secukinumab 150 mg and 1.72 per 100 patient-years in the placebo arm. In the PsA cohort (N = 2453), the incidence rate for uveitis was 0.71 per 100 patient-years in the secukinumab 300 mg arm; no events were reported in the placebo arm. Conclusion: During the placebo-controlled phase, a numerically lower incidence of uveitis was observed in secukinumab-treated axSpA patients. In PsA patients, the incidence was low in secukinumab-treated patients, while uveitis was not reported in the placebo group.

Background Interleukin-17A (IL17A) is a proinflammatory cytokine critically involved in autoimmune diseases, and monoclonal antibodies of IL17A have been approved for clinical treatment of psoriasis. However, a usable psoriatic animal model has been always required for preclinical evaluation of IL17A antagonists. Imiquimod (IMQ)-induced psoriasis model is widely used in fundamental research, but it’s not able to accurately show anti-psoriatic effect of IL17A antagonists with conventional modelling condition. Results On female C57BL/6 mice, with optimization on the usage of IMQ, positive control reagent and anti-mIL17A antibody, a 7-day model with proper testing window, acceptable disease severity as well as high repeatability was developed, and the efficacy of IL17A antagonist can be objectively evaluated by several qualitative and quantitative indices. Meanwhile, we validated the detailed involvement of IL17A signaling in disease progression, confirmed that the expression levels of IL17A and its related cytokines were induced by IMQ application, and its downstream cytokines can be inhibited by IL17A antagonist treatment. In further study, we revealed that IL17A was transient induced by IMQ and directly caused downstream signaling activation. This finding on the kinetical change of IL17A signaling will manifest the pharmacokinetics-pharmacodynamics investigation of IL17A antagonists. Conclusions Our work presents the application of a convenient psoriatic animal model in the research and development of IL17A antagonists, meanwhile providing extra evidence for understanding IL17A’s role in the progression of IMQ-induced psoriasis model, which manifest the research and development of IL17A antagonists.

The underlying pathophysiology linking psoriasis vulgaris (PV) and metabolic syndrome (MetS) is not fully understood. The present study aimed to investigate the serum level of interleukin (IL)-9 and tissue levels of IL-9 and its receptor in PV patients with MetS and analyze the correlation of IL-9 levels with psoriasis disease severity and MetS.PurposeThe underlying pathophysiology linking psoriasis vulgaris (PV) and metabolic syndrome (MetS) is not fully understood. The present study aimed to investigate the serum level of interleukin (IL)-9 and tissue levels of IL-9 and its receptor in PV patients with MetS and analyze the correlation of IL-9 levels with psoriasis disease severity and MetS.This study enrolled 75 PV patients with MetS, 57 PV patients without MetS, 20 healthy blood donors, and 7 healthy skin donors. Clinical, socio-demographic, and anthropometric data were obtained from all individuals. Fasting blood glucose, insulin, lipid profile levels, and serum levels of IL-9 and IL-17A were measured. The expression of IL-9 and its receptor in skin specimens in PV patients and healthy controls was determined using immunohistochemistry. Normal human epidermal keratinocytes were stimulated with five pro-inflammatory cytokines (tumor necrosis factor-α, oncostatin M, IL-22, IL-17A, and IL-1α) to establish a psoriatic keratinocyte model and subsequently treated with IL-9. Their mRNA levels of antimicrobial peptides and chemokines were measured using quantitative real-time polymerase chain reaction.MethodsThis study enrolled 75 PV patients with MetS, 57 PV patients without MetS, 20 healthy blood donors, and 7 healthy skin donors. Clinical, socio-demographic, and anthropometric data were obtained from all individuals. Fasting blood glucose, insulin, lipid profile levels, and serum levels of IL-9 and IL-17A were measured. The expression of IL-9 and its receptor in skin specimens in PV patients and healthy controls was determined using immunohistochemistry. Normal human epidermal keratinocytes were stimulated with five pro-inflammatory cytokines (tumor necrosis factor-α, oncostatin M, IL-22, IL-17A, and IL-1α) to establish a psoriatic keratinocyte model and subsequently treated with IL-9. Their mRNA levels of antimicrobial peptides and chemokines were measured using quantitative real-time polymerase chain reaction.Serum level of IL-9 and tissue levels of IL-9 and its receptor were upregulated in PV patients with MetS. IL-9 level was positively correlated to IL-17A level; however, no significant correlation of IL-9 level with psoriasis area severity index was observed. IL-9 level had a positive correlation with the presence of MetS and its components. Correspondingly, IL-9 level positively correlated with waist circumference, body mass index, homeostasis model assessment-insulin resistance, blood pressure, and triglyceride level and negatively correlated with high-density lipoprotein cholesterol level. Additionally, IL-9 stimulated the expression of antimicrobial peptides and chemokines in a psoriatic keratinocyte model.ResultsSerum level of IL-9 and tissue levels of IL-9 and its receptor were upregulated in PV patients with MetS. IL-9 level was positively correlated to IL-17A level; however, no significant correlation of IL-9 level with psoriasis area severity index was observed. IL-9 level had a positive correlation with the presence of MetS and its components. Correspondingly, IL-9 level positively correlated with waist circumference, body mass index, homeostasis model assessment-insulin resistance, blood pressure, and triglyceride level and negatively correlated with high-density lipoprotein cholesterol level. Additionally, IL-9 stimulated the expression of antimicrobial peptides and chemokines in a psoriatic keratinocyte model.Our findings confirmed that higher IL-9 level is associated with PV complicated by MetS, suggesting that IL-9 may be a link between PV and MetS.ConclusionOur findings confirmed that higher IL-9 level is associated with PV complicated by MetS, suggesting that IL-9 may be a link between PV and MetS.

We aimed to perform a structured literature review of spinal radiographic progression, as assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), in patients with ankylosing spondylitis (AS) or nonradiographic axial spondyloarthritis (nr-axSpA) treated with biologic therapy. Searches were limited to English language manuscripts published in the 11 years prior to 9 July 2019. Randomized controlled trials, open-label extensions (OLEs) and observational studies reporting mSASSS progression in patients with AS or nr-axSpA treated with biologics were eligible for inclusion. Bias was assessed using the methodological index for nonrandomized studies (MINORS) tool. Among the 322 studies identified in the literature search, 23 (11 OLEs and 12 cohort studies) met the eligibility criteria and were selected for inclusion. Most studies reported mSASSS progression in patients with AS receiving tumor necrosis factor inhibitor (TNFi) treatment. One study reported mSASSS progression in patients with AS treated with secukinumab, an interleukin-17A inhibitor. The mean (range) MINORS score was 11.3 (7–15) for the 15 noncomparative studies and 15 (12–22) for the 8 comparative studies. Although results of the individual studies were variable, mSASSS progression in patients with AS was generally minimal and slow with long-term TNFi therapy. Moreover, odds ratios for the likelihood of mSASSS progression with/without TNFi favoured TNFi therapy in several of the cohort studies. The rate of mSASSS progression following continuous secukinumab treatment was low and remained stable over 4 years. Of two studies reporting progression in patients with nr-axSpA treated with TNFis, one showed no mSASSS progression; however, the lack of control limited comparative conclusions.