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Aims and methodsAccurate protein measurements using formalin-fixed biopsies are needed to improve disease characterisation. This feasibility study used targeted and global mass spectrometry (MS) to interrogate a spectrum of disease severities using 19 ulcerative colitis (UC) biopsies.ResultsTargeted assays for CD8, CD19, CD132 (interleukin-2 receptor subunit gamma/common cytokine receptor gamma chain), FOXP3 (forkhead box P3) and IL17RA (interleukin 17 receptor A) were successful; however, assays for IL17A (interleukin 17A), IL23 (p19) (interleukin 23, alpha subunit p19) and IL23R (interleukin 23 receptor) did not permit target detection. Global proteome analysis (4200 total proteins) was performed to identify pathways associated with UC progression. Positive correlation was observed between histological scores indicating active colitis and neutrophil-related measurements (R2=0.42–0.72); inverse relationships were detected with cell junction targets (R2=0.49–0.71) and β-catenin (R2=0.51–0.55) attributed to crypt disruption. An exploratory accuracy assessment with Geboes Score and Robarts Histopathology Index cut-offs produced sensitivities/specificities of 72.7%/75.0% and 100.0%/81.8%, respectively.ConclusionsPathologist-guided MS assessments provide a complementary approach to histological scoring systems. Additional studies are indicated to verify the utility of this novel approach.

SummaryInterleukin 17A (IL17A) is reported to be involved in many inflammatory processes, but its role in aortic valve diseases remains unknown. We examined the role of IL17A based on an ApoE−/− mouse model with strategies as fed with high-fat diet or treated with IL17A monoclonal antibody (mAb). 12 weeks of high-fat diet feeding can elevate cytokines secretion, inflammatory cells infiltration and myofibroblastic transition of valvular interstitial cells (VICs) in aortic valve. Moreover, diet-induction accelerated interleukin 17 receptor A (IL17RA) activation in VICs. In an IL17A inhibition model, the treatment group was intra-peritoneally injected with anti-IL17A mAb while controls received irrelevant antibody. Functional blockade of IL17A markedly reduced cellular infiltration and transition in aortic valve. To investigate potential mechanisms, NF-κB was co-stained in IL17RA+ VICs and IL17RA+ macrophages, and further confirmed by Western blotting in VICs. High-fat diet could activate NF-κB nuclear translocation in IL17RA+ VICs and IL17RA+ macrophages and this process was depressed after IL17A mAb-treatment. In conclusion, high-fat diet can lead to IL17A upregulation, VICs myofibroblastic transition and inflammatory cells infiltration in the aortic value of ApoE−/− mice. Blocking IL17A with IL17A mAb can alleviate aortic valve inflammatory states.

BackgroundThe interleukin 17 receptor E (IL-17RE) is specific for the epithelial cytokine interleukin-17C (IL-17C). Asthma exacerbations are frequently caused by viral infections. Polyinosinic:polycytidylic acid (pIC) mimics viral infections through binding to pattern recognition receptors (e.g. TLR-3). We and others have shown that pIC induces the expression of IL-17C in airway epithelial cells. Using different mouse models, we aimed to investigate the function of IL-17RE in the development of experimental allergic asthma and acute exacerbation thereof.MethodsWild-type (WT) and IL-17RE deficient (Il-17re−/−) mice were sensitized and challenged with OVA to induce allergic airway inflammation. pIC or PBS were applied intranasally when allergic airway inflammation had been established. Pulmonary expression of inflammatory mediators, numbers of inflammatory cells, and airway hyperresponsiveness (AHR) were analyzed.ResultsAblation of IL-17RE did not affect the development of OVA-induced allergic airway inflammation and AHR. pIC induced inflammation independent of IL-17RE in the absence of allergic airway inflammation. Treatment of mice with pIC exacerbated pulmonary inflammation in sensitized and OVA-challenged mice in an IL-17RE-dependent manner. The pIC-induced expression of cytokines (e.g. keratinocyte-derived chemokine (KC), granulocyte-colony stimulating factor (G-CSF)) and recruitment of neutrophils were decreased inIl-17re−/−mice. pIC-exacerbated AHR was partially decreased inIl-17re−/−mice.ConclusionsOur results indicate that IL-17RE mediates virus-triggered exacerbations but does not have a function in the development of allergic lung disease.

While biologic therapies for psoriasis are effective for many patients, some patients may lose response, have inadequate control of disease, or develop intolerance to certain biologic agents. It may therefore be beneficial for patients whose psoriasis fails to respond to one biologic to switch to a different biologic therapy, in particular one with a different mechanism of action. However, it remains unclear how prior biologic exposure or lack of response affects the efficacy and safety of subsequent biologics in patients with moderate-to-severe psoriasis. Brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, has previously been shown to be efficacious in treating moderate-to-severe psoriasis in three large phase 3 trials (AMAGINE-1, AMAGINE-2, and AMAGINE-3). In this review, we summarize the efficacy and safety of brodalumab in patients with moderate-to-severe psoriasis and a history of biologic exposure. Further, we describe improvements in skin clearance and quality of life measures as well as safety in patients who had inadequate response to ustekinumab and who were rescued with brodalumab therapy. Lastly, we discuss improvements in skin clearance following rescue with brodalumab in patients whose disease failed to respond to secukinumab and ixekizumab. The findings of our review suggest that brodalumab is a safe and efficacious treatment regardless of past biologic use or lack of response to prior biologic therapy.

Interleukin (IL)-17A, a pro-inflammatory cytokine that is linked to the pathology of several inflammatory diseases, has been shown to be upregulated in early human tendinopathy and to mediate inflammatory and tissue remodelling events. However, it remains unclear which cells in tendons can respond to IL-17A, and how IL-17A, and its family members IL-17F and IL-17AF, can affect intracellular signalling activation and mRNA expression in healthy and diseased tendon-derived fibroblasts. Using well-phenotyped human tendon samples, we show that IL-17A and its receptors IL-17RA and IL-17RC are present in healthy hamstring, and tendinopathic and torn supraspinatus tendon tissue. Next, we investigated the effects of IL-17A, IL-17F, or IL-17AF on cultured patient-derived healthy and diseased tendon-derived fibroblasts. In these experiments, IL-17A treatment significantly upregulated IL6, MMP3, and PDPN mRNA expression in diseased tendon-derived fibroblasts. IL-17AF treatment induced moderate increases in these target genes, while little change was observed with IL-17F. These trends were reflected in the activation of intracellular signalling proteins p38 and NF-κB p65, which were significantly increased by IL-17A, modestly increased by IL-17AF, and not increased by IL-17F. In combination with TNF-α, all three IL-17 cytokines induced IL6 and MMP3 mRNA expression to similar levels. Therefore, this study confirms that healthy and diseased tendon-derived fibroblasts are responsive to IL-17 cytokines and that IL-17A induces the most profound intracellular signalling activation and mRNA expression of inflammatory genes, followed by IL-17AF, and finally IL-17F. The ability of IL-17 cytokines to induce a direct response and activate diverse pro-inflammatory signalling pathways through synergy with other inflammatory mediators suggests a role for IL-17 family members as amplifiers of tendon inflammation and as potential therapeutic targets in tendinopathy.

It is known that the microbiome affects human physiology, emotion, disease, growth, and development. Most humans exhibit reduced appetites under high temperature and high humidity (HTHH) conditions, and HTHH environments favor fungal growth. Therefore, we hypothesized that the colonic mycobiota may affect the host’s appetite under HTHH conditions. Changes in humidity are also associated with autoimmune diseases. In the current study mice were fed in an HTHH environment (32°C ± 2°C, relative humidity 95%) maintained via an artificial climate box for 8 hours per day for 21 days. Food intake, the colonic fungal microbiome, the feces metabolome, and appetite regulators were monitored. Components of the interleukin 17 pathway were also examined. In the experimental groups food intake and body weight were reduced, and the colonic mycobiota and fecal metabolome were substantially altered compared to control groups maintained at 25°C ± 2°C and relative humidity 65%. The appetite-related proteins LEPT and POMC were upregulated in the hypothalamus (p < 0.05), and NYP gene expression was downregulated (p < 0.05). The expression levels of PYY and O-linked β-N-acetylglucosamine were altered in colonic tissues (p < 0.05), and interleukin 17 expression was upregulated in the colon. There was a strong correlation between colonic fungus and sugar metabolism. In fimo some metabolites of cholesterol, tromethamine, and cadaverine were significantly increased. There was significant elevation of the characteristic fungi Solicoccozyma aeria, and associated appetite suppression and interleukin 17 receptor signaling activation in some susceptible hosts, and disturbance of gut bacteria and fungi. The results indicate that the gut mycobiota plays an important role in the hypothalamus endocrine system with respect to appetite regulation via the gut-brain axis, and also plays an indispensable role in the stability of the gut microbiome and immunity. The mechanisms involved in these associations require extensive further studies.

In the intestine, the host must be able to control the gut microbiota and efficiently absorb transiently supplied metabolites, at the risk of enormous infection. In mammals, the inflammatory cytokine interleukin (IL)-17A/F is one of the key mediators in the intestinal immune system. However, many functions of IL-17 in vertebrate intestines remain unclarified. In this study, we established a gene-knockout (KO) model of IL-17 receptor A1 (IL-17RA1, an IL-17A/F receptor) in Japanese medaka (Oryzias latipes) using genome editing technique, and the phenotypes were compared to wild type (WT) based on transcriptome analyses. Upon hatching, homozygous IL-17RA1-KO medaka mutants showed no significant morphological abnormality. However, after 4 months, significant weight decreases and reduced survival rates were observed in IL-17RA1-KO medaka. Comparison of gene-expression patterns in WT and IL-17RA1-KO medaka revealed that various metabolism- and immune-related genes were significantly down-regulated in IL-17RA1-KO medaka intestine, particularly genes related to mevalonate metabolism (mvda, acat2, hmgcs1, and hmgcra) and genes related to IL-17 signaling (such as il17c, il17a/f1, and rorc) were found to be decreased. Conversely, expression of genes related to cardiovascular system development, including fli1a, sox7, and notch1b in the anterior intestine, and that of genes related to oxidation–reduction processes including ugp2a, aoc1, and nos1 in posterior intestine was up-regulated in IL-17RA1-KO medaka. These findings show that IL-17RA regulated immune- and various metabolism-related genes in the intestine for maintaining the health of Japanese medaka.

Brodalumab is one of the most efficacious biologic agents available for psoriasis. It also has a unique mechanism; it is the only agent that blocks the entire interleukin 17 receptors instead of blocking individual cytokines. However, the main drawback is that brodalumab has an FDA mandated black box warning regarding suicide. This is an up-to-date article reviews the scientific validity of this issue with brodalumab and suicide. Areas covered: A worldwide literature search was conducted on the above issue regarding suicide risk and brodalumab. All relevant articles on this topic searchable in public domain were utilized. Expert opinion: The FDA black box warning is based on three completed suicides that happened in one research location out of 390 research sites worldwide. All three completed suicides have alternative explanations unrelated to brodalumab. The overall data from phase III clinical trials shows that psoriasis patients recorded significant improvement in depression after treatment with brodalumab. The overall impression is that the suicide issue is far from being scientifically validated and this is why the FDA itself stated in the package insert that "the cause and effect relationship these suicides and brodalumab has not been established."

Palmoplantar pustular psoriasis, also termed palmoplantar pustulosis (PPP), is a rare disease affecting the palmoplantar regions characterized by sterile, yellow to brown pustules mostly on erythematous skin. PPP is related to a high burden due to painful, impaired and stigmatizing character. Several isoforms of interleukin (IL) have been implicated in its pathophysiology. Here, we report on four patients with PPP treated with the novel IL-17 receptor A blocker brodalumab, in whom this therapy was not successful or showed moderate improvement combined with adverse events.

Background: Myocardial ischemia reperfusion (I/R) is characterized by a complex inflammatory response that stimulates the formation of inflammasome and production of Interleukin-1β (IL-1β). As a decoy receptor for IL-1β, the role of Interleukin-1 receptor type 2 (IL-1R2) in myocardial I/R injury is still unclear. Here, for the first time, we report the underlying mechanisms of IL-1R2 in protecting cardiomyocyte against I/R injury. Methods: Initially, the expression of IL-1R2 in myocardial I/R injury was determined by RT-PCR and western blot assays. IL-1R2-deficiency mice and AAV-9 virus carrying IL-1R2 under cTnT promoter were administrated to identify the protective role of IL-1R2 and RNA-sequencing was performed to explore the underlying mechanisms of IL-1R2 in myocardial I/R injury. Besides, neonatal rat ventricular myocytes (NRVM) were isolated to investigate the relationships of IL-1R2, NLRP3 inflammasome and Interleukin 17 receptor A (IL-17RA). Findings: We demonstrated that the expression of IL-1R2 in cardiomyocyte was induced by I/R injury both in vivo and in vitro. IL-1R2-deficient mice decreased cardiac systolic function, increased infarct size and cardiomyocyte apoptosis. Whereas, Overexpression of IL-1R2 in cardiomyocyte protected cardiomyocyte against I/R-induced cell death through reducing the NLRP3 inflammasome activation and IL-17RA expression both in vivo and in vitro. Interpretation: Collectively, the upregulation of IL-1R2 in cardiomyocyte provides therapeutic effects in protecting cardiomyocyte against cell death during myocardial I/R injury. Funding: Natural Key Research and Development Project of Zhejiang Province, China (2018C03015), National Key Research and Development Program of China (2016YFC1102203), Zhejiang Provincial Natural Science Foundation of China under Grant (LQ17H020002). Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: The collection of blood plasma from AMI patients and healthy controls was conducted with approval from the Institutional Animal Care and Use Committee, and all animal studies were conducted with approval from the Medical Ethics Committee of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine.

In the intestine, the host must be able to control the gut microbiota and efficiently absorb transiently supplied metabolites, at the risk of enormous infection. In mammals, the inflammatory cytokine interleukin (IL)-17A/F is one of the key mediators in the intestinal immune system. However, many functions of IL-17 in vertebrate intestines remain unclarified. In this study, we established a gene-knockout (KO) model of IL-17 receptor A1 (RA1), an IL-17A/F receptor, in Japanese medaka (Oryzias latipes) using genome editing technique and the phenotypes were compared to wild type (WT) based on transcriptome analyses. Upon hatching, homozygous IL-17RA1-KO medaka mutants showed no significant morphological abnormality. However, after 4 months, significant weight decreases and reduced survival rates were observed in IL-17RA1-KO medaka. Comparing gene-expression patterns in WT and IL-17RA1-KO medaka revealed that various metabolism- and immune-related genes were significantly down-regulated in IL-17RA1-KO medaka intestine, particularly genes related to mevalonate metabolism (mvda, acat2, hmgcs1, and hmgcra) and genes related to IL-17 signaling (such as il17c, il17a/f1, and rorc) were found to be decreased. These findings show that IL-17RA regulated immune- and various metabolism-related genes in the intestine for maintaining the health of Japanese medaka.

The proinflammatory cytokines IL-17A and IL-17F have been identified as key drivers of a range of human inflammatory diseases, such as psoriasis, which has led to several therapeutic antibodies targeted at IL-17A. The two cytokines have been shown to tightly associate as functional homo and hetero dimers, which induce signalling via the formation of a cell surface signalling complex with a single copy of both IL-17RA and IL-17RC. Striking differences in affinity have been observed for IL-17RA binding to IL-17AA, IL-17AF and IL-17FF, however, the functional significance and molecular basis for this has remained unclear. We have obtained comprehensive backbone NMR assignments for full length IL-17AA (79%), IL-17AF (93%) and IL-17FF (89%), which show that the dimers adopt almost identical backbone topologies in solution to those observed in reported crystal structures. Analysis of the line widths and intensities of assigned backbone amide NMR signals has revealed striking differences in the conformational plasticity and dynamics of IL-17AA compared to both IL-17AF and IL-17FF. Our NMR data indicate that a number of regions of IL-17AA are interconverting between at least two distinct conformations on a relatively slow timescale. Such conformational heterogeneity has previously been shown to play an important role in the formation of many high affinity protein-protein complexes. The locations of the affected IL-17AA residues essentially coincides with the regions of both IL-17A and IL-17F previously shown to undergo significant structural changes on binding to IL-17RA. Substantially less conformational exchange was revealed by the NMR data for IL-17FF and IL-17AF. We propose that the markedly different conformational dynamic properties of the distinct functional IL-17 dimers plays a key role in determining their affinities for IL-17RA, with the more dynamic and plastic nature of IL-17AA contributing to the significantly tighter affinity observed for binding to IL-17RA. In contrast, the dynamic properties are expected to have little influence on the affinity of IL-17 dimers for IL-17RC, which has recently been shown to induce only small structural changes in IL-17FF upon binding.

BACKGROUND Chronic spontaneous urticaria (CSU) is a distressing skin disease. Family clustering and heterogeneity in the onset and progression indicate that susceptibility to CSU is a complex trait. In this study, we performed haplotype analysis for one of the key player gene, IL17RA, for CSU to test the association with disease susceptibility and severity. METHODOLOGY The study included 70 CSU patients and 30 healthy controls. The severity of the disease was evaluated by autologous serum skin test (ASST) and urticaria activity score (UAS). ASST test was done and quality of life was assessed using a questionnaire. Allelic discrimination analysis for rs4819554 and rs879577 was performed using real-time polymerase chain reaction technology. RESULTS Carriers of rs4819554*G were more prone to develop CSU than its counterpart (P = .039), while rs4819554*A allele displayed more severe phenotype in the form of more prolonged disease duration (P = .040), concurrent angioedema (P

Background: Chronic spontaneous urticaria (CSU) is a distressing skin disease. Family clustering and heterogeneity in the onset and progression indicate that susceptibility to CSU is a complex trait. In this study, we performed haplotype analysis for one of the key player gene, IL17RA, for CSU to test the association with disease susceptibility and severity.MethodsThe study included 70 CSU patients and 30 healthy controls. The severity of the disease was evaluated by autologous serum skin test (ASST) and urticaria activity score (UAS). ASST test was done and quality of life was assessed using a questionnaire. Allelic discrimination analysis for rs4819554 and rs879577 was performed using Real-Time Polymerase Chain Reaction technology.Results: Carriers of rs4819554*G were more prone to develop CSU than its counterpart (p = 0.039), while rs4819554*A allele displayed more severe phenotype in the form of more prolonged disease duration (p = 0.040), concurrent angioedema (p < 0.001), higher level of treatment (p < 0.001), and higher score of quality of life (p < 0.001). Additionally, homozygote patients with rs879577*CC were associated with angioedema (p < 0.001). Haplotype analysis revealed that cohorts with both rs4819554*A and rs879577*T conferred protection against developing CSU (OR = 0.07, 95%CI = 0.01 - 0.32, p = 0.001).Conclusions: Our results showed that IL17RA gene polymorphisms might contribute to the increased susceptibility to CSU.

Vibrio harveyi is regarded as serious pathogen for marine fishes. To evaluate the physiological responses of spotted sea bass (Lateolabrax maculatus) after V. harveyi infection, four biochemical biomarkers including alanine amino transferase (ALT), albumin (ALB), total protein (TP) and glucose (GLU) were measured in serum. Our results showed that V. harveyi infection significantly influenced the concentration of ALT, ALB and GLU. Additionally, five interleukin-17 (IL-17) and five IL-17 receptors (IL-17R) genes were identified in spotted sea bass and their gene structures were characterized. Furthermore, the expression patterns of IL-17 and IL-17R genes were determined by qPCR in liver, intestine, spleen and head kidney after V. harveyi infection. All IL-17 and IL-17R genes exhibited time- and tissue-dependent expressions. Several tested genes were dramatically induced by V. harveyi treatment, particularly IL-17A/F1 in liver and head kidney, IL-17A/F2 in head kidney, IL-17RC in spleen with more than 10-fold increases, which suggested their potential essential roles against bacterial infection.

Visual Abstract, Highlights • Moderate renal impairment significantly increases atherosclerotic lesion size and leukocyte numbers, most markedly macrophages and T cells, in LDLr–/– mice. • IL-17 receptor A–deficient LDLr–/– mice are protected from the growth in lesion size and leukocyte infiltrate in renal impairment. • Monocytes, especially Ly6C/GR1HIGH cells, express high levels of IL-17 receptor A. • IL-17A increases monocyte adhesion to the aortic wall and enhances endothelial cell pro-inflammatory cytokine production. • Ablation of IL-17A or IL-17A blockade normalizes the inflammatory aortic wall infiltrate even in established atherosclerosis., Summary Effective therapy of atherosclerotic complications in patients with chronic kidney disease (CKD) is an unmet clinical need. Cardiovascular events are the most common cause of death. At a glomerular filtration rate ≤60 ml/min, these events are increased also after correction for common risk factors. Previous studies have reported enhanced vascular inflammation in mice and recently also in humans. Our current data show, in a mouse model of atherosclerosis in moderate renal impairment, that interleukin-17 receptor A is instrumental in this condition, and blockade of this pathway can normalize arterial inflammation even in advanced atherosclerosis.

The mutual relationship between the intestinal immune system and the gut microbiota has received a great deal of attention. In mammals, interleukin-17A and F (IL-17A/F) are inflammatory cytokines and key regulators of the gut microbiota. However, in teleosts, the function of IL-17A/F in controlling the gut microbiota is poorly understood. We attempted to elucidate the importance of teleost IL-17 signaling in controlling gut microbiota. We previously established a knockout (KO) of IL-17 receptor A (RA) 1, a receptor for IL-17A/F, in the Japanese medaka (Oryzias latipes) using the CRISPR-Cas9 system and performed 16S rRNA-based metagenomic analyses using the anterior and posterior sections of the intestinal tract. The number of observed OTUs in the anterior intestine was significantly decreased in IL-17RA1 KO medaka compared to that in the wild-type (WT). Furthermore, β-diversity analysis (weighted UniFrac) revealed considerably different bacterial composition in the anterior intestine of IL-17RA1 KO compared to WT, with similar findings in α-diversity. Notably, the pathogen Plesiomonas shigelloides was significantly increased in the posterior intestine of IL-17RA1 KO medaka. These findings indicate that signaling via IL-17RA1 is required to maintain a healthy gut microbiota in teleosts and mammals. The involvement of IL-17RA1 in controlling the gut microbiota has been demonstrated, resulting in microbiome dysbiosis in IL-17RA1 KO medaka.

Interleukin-17 (IL-17) is a cytokine secreted by a variety of immune cells that plays an important role in host defense against pathogens. IL-17 usually activates downstream immune signaling pathway by binding to heterodimeric or homodimeric complex formed by IL-17 receptors (IL-17R). Describing the characteristics, tissue distribution of IL-17 and IL-17 receptor family members and their expression after pathogen infection will provide a reference for host defense against disease of turbot. In this study, six IL-17 family members and nine IL-17 receptor family members were identified by analyzing the turbot (Scophthalmus maximus) genome. Different from other vertebrates, most members of the IL-17 receptor family own two copies. Protein structure analysis showed that the six IL-17 family members contained typical "IL-17" domains, and the nine IL-17 receptor family members contained typical "SEFIR domain" or "IL17_R_N domain". Syntenic analysis revealed that all IL-17s and IL-17Rs were chromosomally conserved compared with other fish. The phylogenetic analysis further confirmed the evolutionary conservatism of different copies of IL-17C and IL-17Rs. Tissue distribution results showed that IL-17 and IL-17R genes were highly expressed in immune-related tissues. The expression of IL-17C and its receptor in the mucosal immune tissues after infection with V. anguillarum was analyzed subsequently. The results showed that they were significantly increased in the skin, the first tissue to resist V. anguillarum. The results are consistent with previous studies showing that IL-17 and IL-17 receptor play an important role in promoting innate immune response.

Pouchitis is the most common long-term complication of restorative proctocolectomy with ileal pouch-anal anastomosis. We investigated alterations in the expression of microRNAs, noncoding RNAs that act as potent negative regulators of gene expression, in pouchitis. The subjects of this study were 16 patients with diagnosed pouchitis and 48 patients without pouchitis after restorative proctocolectomy, performed for ulcerative colitis. Total RNA was extracted from biopsies and microRNAs were quantified using a real-time polymerase chain reaction. The expression of microRNA 21 and 223 was higher, whereas that of microRNA 192 and 196a was lower, in the inflamed mucosa from the pouchitis patients than in the mucosa from the non-pouchitis patients. The levels of 14 microRNAs were significantly lower in the mucosa from the pouchitis patients, than in the non-inflamed proximal ileal mucosal samples. The expression of microRNA 192 was remarkably reduced in pouchitis. A significant negative correlation was found between microRNA 192 and interleukin 17 receptor A mRNA levels. Significant alteration in miRNA expression in line with inflammatory bowel disease was evident in the mucosa from the pouchitis patients. Interleukin 17 receptor A may be involved in the pathogenesis of pouchitis through the downregulation of microRNA 192.

In mammals, interleukin 17 (IL-17), which is produced mainly by Th17 cells, is a hallmark inflammatory cytokine that plays key roles in the protection against infection and intestinal mucosal immunity. The mammalian IL-17 receptor family comprises five members (IL-17RA–E). Of these, IL-17RA is important in the control of the bacterial microbiota in mucosal tissues, particularly in the intestine, where it acts as a receptor for IL-17A and -F. In this study, the nucleotide sequence of IL-17RA1 cDNA from Japanese medaka (Oryzias latipes) of the Cab strain was determined and compared to two IL-17RA cDNAs (i.e., IL-17RA1 and IL-17RA2) of Japanese medaka Hd-rR strain downloaded from NCBI. Hd-rR 17RA1 and IL-17RA2 were located on chromosome 23 and chromosome 6, respectively, and phylogenetic tree analysis revealed that teleost IL-17RA1 and IL-17RA2 were separated in different clusters. Synteny analysis revealed that Japanese medaka IL-17RA1 and mammalian IL-17RA are conserved. IL-17RA1 expression levels in the gills, intestine, whole kidney, skin, and spleen were significantly higher than those of IL-17RA2, suggesting that IL-17RA1 is an important functional receptor in mucosal immunity. Interestingly, the expression levels of both IL-17RA genes were notably higher in the posterior than in the anterior intestinal tract section. Furthermore, despite its lower basal expression, IL-17RA2 expression was significantly increased at 72 h post Edwardsiella tarda infection.

Introduction: Interleukin 17 receptor E (IL-17RE) is specific to the epithelial cytokine interleukin-17C (IL-17C). Asthma exacerbation are frequently caused by viral infections. Polycytidylic acid (poly(I:C)) mimics viral infections through binding to TLR-3. We and others have shown that poly(I:C) induces the expression of IL-17C in respiratory epithelial cells. Aim: To investigate the function of IL-17RE in a mouse model of allergic lung inflammation. Methods: Wildetyp (WT) and IL-17RE deficient mice were sensitized and challenged with OVA to induce allergic lung inflammation. PolyI:C was applied intranasally. Levels of pulmonary cytokines and chemokines were analyzed 24 hours post polyI:C treatment. Results: There were no differences in the pulmonary concentrations of the cytokines CCL5, IL-5, and IL-13 and the chemokines MIP-2 and KC between WT and IL-17RE-/- mice in the absence of allergic lung inflammation 24 hours post polyI:C treatment. Treatment with polyI:C in the presence of allergic lung inflammation resulted in significantly increased concentrations of IL-15, IL-13, CCL5, MIP-2, and KC in WT mice compared with IL-17RE-/- mice. Summary: These results indicate that IL-17RE mediates virus-triggered lung inflammation in experiment asthma.

Sound evidence supports a role for interleukin‐17 (IL‐17) ‐producing γδ T cells and IL‐17‐producing helper T (Th17) cells in intestinal homeostasis, especially in intestinal barrier integrity. In the present study, we aimed to evaluate the role of IL‐17 cytokine in the regulation of intestinal immunity and obesity‐induced metabolic syndrome (MetS) in an experimental murine model. C57BL/6 wild‐type (WT) mice and mice lacking the IL‐17 cytokine receptor (IL‐17RA(−/−)) were fed either a control diet (CD) or a high‐fat diet (HFD) for 9 weeks. Our data demonstrate that IL‐17RA(−/−) mice are protected against obesity, but develop hyperglycemia, hyperinsulinemia and insulin resistance. In parallel, HFD‐fed IL‐17RA(−/−) mice display intense inflammation in the ileum compared with WT mice on the HFD. IL‐17RA(−/−) mice fed the HFD exhibit impaired neutrophil migration to the intestinal mucosa and reduced gene expression of the CXCL‐1 chemokine and CXCR‐2 receptor in the ileum. Interestingly, the populations of neutrophils (CD11b(+) Ly6G(+)) and anti‐inflammatory macrophages (CD11b(+) CX3CR1(+)) are increased in the mesenteric lymph nodes of these mice. IL‐17RA(−/−) mice on the HFD also display increased commensal bacterial translocation into the bloodstream and elevated lipopolysaccharide (LPS) levels in the visceral adipose tissue (VAT). Metagenomic analysis of bacterial 16S gene revealed increased Proteobacteria and Bacteroidetes phyla, the main representatives of Gram‐negative bacteria, and reduced Akkermansia muciniphila in the fecal samples of IL‐17RA(−/−) mice fed the HFD. Together, these data indicate that the IL‐17/IL‐17R axis drives intestinal neutrophil migration, limits gut dysbiosis and attenuates LPS translocation to VAT, resulting in protection to MetS.

Interleukin-17 receptor A (IL-17RA) has been recognized as a valuable biomarker for diverse diseases, including autoimmune diseases. In this work, an electrochemical biosensor with great sensitivity and selectivity toward IL-17RA was fabricated using an IL-17RA aptamer (Kd=14.00nM) for the first time. The aptasensor was manufactured using electrodeposition of gold nanoparticles, and then quantitative detection of IL-17RA was performed based on impedimetry. The developed sensor exhibited a superior analytical performance for IL-17RA with a wide dynamic range of 10-10,000pg/mL in buffer and a detection limit of 2.13pg/mL, which is lower than that of commercially available ELISA kits. In addition, we validated the high specificity of the designed aptasensor to only IL-17RA, which showed good sensitivity even in human serum solution. Furthermore, the detection of the differentiated HL-60 cells expressing IL-17RA was successfully performed. Clinical applicability of the sensor was also demonstrated utilizing neutrophils separated from asthma patients. It is expected that the fabricated aptasensor will become an excellent diagnostic platform for IL-17RA-mediated diseases.

Introduction: Oral Lichen Planus (OLP) is considered a T cell mediated disease with unknown etiology. T helper cells appear to play an important role in the pathogenesis of OLP.Interleukin-17 (IL-17) is the signature cytokine of T helper (Th) cells. Recent studies suggested that IL-17 may be involved in the pathogenesis of OLPand homeostasis of tissues beyond the immune system.Interleukin-17 receptor (IL-17R) expression is working in disparate tissuessuch as articular cartilage, bone, meniscus, brain, hematopoietic tissue, kidney, lung, skin and intestine. Aim of the study: This study evaluated the possible correlation between serum and tissue levels of IL-17 as well as the expression of its tissue receptor in order to detect their possible role in the etio-pathogenesis of OLP. Subjects and methods: 20 patients with OLP and 10 healthy volunteers were recruited. Serum and tissue IL-17 levels were assessed by using an Enzyme Linked Immune-Sorbent Assay (ELISA), whileIL-17R gene expression was detected by quantitative real time polymerase chain reaction (qRT-PCR). Results : Results showed that the mean serum and tissue levels of IL-17 as well as mean tissue level of IL-17R in OLP were significantly higher compared to the controls (P value < 0.001),and there was a statistically significant positive (direct) correlation between serum IL-17 andboth tissue level of IL-17 and its tissue receptor. Discussion : This study demonstrated the increased expression of serum and tissue level of IL-17 and IL-17 tissue receptor in OLP patients, suggesting that IL-17 and its receptor in affected tissues may be associated with the pathogenesis of OLP and that IL-17 may be considered an important diagnostic pro-inflammatory cytokine in OLP. Conclusions and recommendations: Further studies are required to investigate the immune-pathologic mechanisms and therapeutic target of IL-17 in OLP.

Sporadic colorectal cancer is one of the most common and lethal cancers worldwide. The locations and functions of immune cells in the colorectal tumor microenvironment are complex and heterogeneous. T-helper (Th)1 cell–mediated responses against established colorectal tumors are associated with better outcomes of patients (time of relapse-free or overall survival), whereas Th17 cell–mediated responses and production of interleukin 17A (IL17A) have been associated with worse outcomes of patients. Tumors that develop in mouse models of colorectal cancer are rarely invasive and differ in many ways from human colorectal tumors. However, these mice have been used to study the mechanisms by which Th17 cells and IL17A promote colorectal tumor initiation and growth, which appear to involve their direct effects on colon epithelial cells. Specific members of the colonic microbiota may promote IL17A production and IL17A-producing cell functions in the colonic mucosa to promote carcinogenesis. Increasing our understanding of the interactions between the colonic microbiota and the mucosal immune response, the roles of Th17 cells and IL17 in these interactions, and how these processes are altered during colon carcinogenesis, could lead to new strategies for preventing or treating colorectal cancer.