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The pathobiology of IL‐17 in lung fibrogenesis is controversial. Here we examined the role of IL‐17A/F in bleomycin (BLM) and adenoviral TGF‐β1‐induced lung fibrosis in mice. In both experimental models, WT and IL17af−/− mice showed increased collagen contents and remodeled lung architecture as assessed by histopathological examination, suggesting that IL‐17A/F is dispensable for lung fibrogenesis. However, IL17af−/− mice responded to the BLM challenge with perturbed lung leukocyte subset recruitment. More specifically, bleomycin triggered angiocentric neutrophilic infiltrations of the lung accompanied by increased mortality of IL17af−/− but not WT mice. WT bone marrow transplantation failed to correct this phenotype in BLM‐challenged IL17af−/− mice. Conversely, IL17a/f−/− bone marrow transplantation → WT did not perturb lung leukocytic responses upon BLM. At the same time, IL17af−/− mice treated with recombinant IL‐17A/F showed an attenuated lung inflammatory response to BLM. Together, the data show that the degree of BLM‐driven acute lung injury was critically dependent on the presence of IL‐17A/F, while in both models, the fibrotic remodeling process was not. [ABSTRACT FROM AUTHOR]

The investigation of enhancer of zeste homolog 1 (Ezh1) in the context of dengue infection immunity has been limited, necessitating further exploration to elucidate its precise role and underlying mechanisms during infections. To address this gap, we generated Ezh1 knockout mice and obtained bone marrow and spleen samples from both Ezh1 knockout mice and wild‐type (WT) counterparts. Leveraging RNA sequencing (RNA‐seq) analysis, we identified the enrichment of genes associated with the interleukin‐17 (IL‐17) signaling pathway among the differentially expressed genes (DEGs) in the spleens of male Ezh1 knockout mice when compared to WT mice. Furthermore, our results revealed that Ezh1 knockout not only curtailed the viral load in dengue virus (DENV) infections but also suppressed the expression of pivotal cytokines, including interleukin‐9 (IL‐9) and IL‐17. Additionally, utilizing high‐parameter flow cytometry, we observed alterations in the immune cell phenotype within the spleens linked to Ezh1 gene knockout. Specifically, Ezh1 knockout inhibited the expressions of programmed cell death protein 1 (PD‐1), lymphocyte‐activation gene 3 (LAG‐3), and cluster of differentiation 86 (CD86). Additionally, we noted a reduction in cluster of differentiation 62L (CD62L) expression in neutrophils following DENV infection. Our comprehensive findings collectively underscore the significant role of Ezh1 in DENV infection, suggesting that targeting Ezh1 could offer a promising antiviral strategy. [ABSTRACT FROM AUTHOR]

Among several quantitative trait loci involved in tuberculosis (TB) control in mice, one was mapped within the chromosome 17 segment occupied by the H2 complex and another within the chromosome 3 segment comprising the S100A8/9 genes, which encode neutrophil inflammatory factor S100A8/9. Previously, we developed a panel of H2‐congenic mouse strains differing by small segments of the major histocompatibility complex Class II (MHC‐II) region from TB‐susceptible H2j mice transferred onto the genetic background of the TB‐resistant C57BL/6 (H2b) strain. Susceptible B6.I‐9.3 mice differ from B6 progenitors by the alleles of their only classical MHC‐II H2‐Aβ gene. The goals of the present study were to: (i) comprehensively characterise the differences in TB‐related phenotypes between mice of the two strains and (ii) decipher interactions between the H2‐Aβ and S100A8/9 genes. Here, we describe the dynamics of TB‐related phenotypes differentiating B6.I‐9.3 and B6 mice (colony forming units counts, histopathology, lung immune cell infiltration and cytokine profiles). We show that disproportionally diminished CD4+ T‐cell population, an enlarged S100A8/9‐positive neutrophil population and higher S100A8/9 serum levels in B6.I‐9.3 mice collectively form the 'susceptible' phenotype before infection. An increase in IL‐17 and a decrease in intrferon‐gamma production by CD4+ T‐cells in these mice provide a mechanistic explanation of this phenotype. Using F2 segregation analysis, we show that the number of S100A8/9‐producing neutrophils in lungs and spleens and the proportion of Th17 CD4+ T‐cells in lungs are significantly lower in the presence of the MHC‐II dominant 'resistant' b allele compared to the recessive 'susceptible' j/j genotype. This provides direct genetic evidence that MHC‐II‐regulated CD4+ T‐cell landscapes determine neutrophil abundance before infection, an important pathogenic factor in TB immunity. [ABSTRACT FROM AUTHOR]

The PD‐1‐PD‐L1 immune checkpoint helps to maintain self‐tolerance and prevent the development of autoimmune diseases. Immune checkpoint inhibitors are successful immunotherapeutics for several cancers, but responding patients can develop immune‐mediated adverse events. It is well established that PD‐1 regulates CD4 and CD8 T‐cell responses, but its role in controlling the activation of pathogenic γδ T cells is less clear. Here we examined the role of PD‐1 in regulating γδ T cells in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. We found that PD‐1 was highly expressed on CD27− Vγ4 γδ T cells in the lymph node (LN) and CNS of mice with EAE. Treatment of mice with anti‐PD‐1 significantly augmented IL‐17A‐producing CD27− Vγ4 γδ T cells in the LN and CNS and enhanced the severity of EAE. The exacerbating effect of anti‐PD‐1 on EAE was lost in Tcrd−/− mice. Conversely, ligation of PD‐1 suppressed Il17a and Rorc gene expression and IL‐17A production by purified Vγ4 γδ T cells stimulated via the TCR, but not with IL‐1β and IL‐23. Our study demonstrates that PD‐1 regulates TCR‐activated CD27− Vγ4 γδ T cells, but that cytokine‐activated IL‐17A producing γδ T cells escape the regulatory effects of the PD‐1‐PD‐L1 pathway. [ABSTRACT FROM AUTHOR]

Aims: Exploring key genes and potential molecular pathways of ferroptosis in immunoglobulin A nephropathy (IgAN). Methods: The IgAN datasets and ferroptosis‐related genes (FRGs) were obtained in the Gene Expression Omnibus (GEO) and FerrDb database. Differentially expressed genes (DEGs) were identified using R software and intersected with FRGs to obtain differentially expressed FRGs (DE‐FRGs). After that, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis (PEA) and Gene Ontology (GO) functional annotation were performed on DE‐FRGs. In the Search Tool for the Retrieval of Interacting Genes (STRING) website, we construct a protein–protein interaction (PPI) network. The PPI network was further investigated with screening hub genes with Cytoscape software. The core genes were then subjected to gene set enrichment analysis (GSEA). Finally, the samples were analyzed for immune infiltration in R, and the correlation between hub genes and immune cells was analyzed. Results: A total of 347 DEGs were identified. CD44, CDO1, CYBB, IL1B, RRM2, AKR1C1, activated transcription factor‐3 (ATF3), CDKN1A, GDF15, JUN, MGST1, MIOX, MT1G, NR4A1, PDK4, TNFAIP3, and ZFP36 were determined as DE‐FRGs. JUN, IL1B, and ATF3 were then screened as hub genes. GSEA and immune infiltration analysis revealed that the hub genes were closely associated with immune inflammatory responses such as NOD‐like receptor signaling, IL‐17 signaling, and TNF signaling. Conclusions: Our results show that JUN and ATF3 are possibly critical genes in the process of IgAN ferroptosis and may be related with immune cell infiltration. [ABSTRACT FROM AUTHOR]

Problem: The interleukin‐17 (IL‐17) family includes pro‐inflammatory cytokines IL‐17A‐F with important roles in mucosal defence, barrier integrity and tissue regeneration. IL‐17A can be dysregulated in fertility complications, including pre‐eclampsia, endometriosis and miscarriage. Because mammalian subclasses (eutherian, metatherian, and prototherian) have different related reproductive strategies, IL‐17 genes and proteins were investigated in the three mammalian classes to explore their involvement in female fertility. Method of Study: Gene and protein sequences for IL‐17s are found in eutherian, metatherian and prototherian mammals. Through synteny and multiple sequence protein alignment, the relationships among mammalian IL‐17s were inferred. Publicly available datasets of early pregnancy stages and female fertility in therian mammals were collected and analysed to retrieve information on IL‐17 expression. Results: Synteny mapping and phylogenetic analyses allowed the classification of mammalian IL‐17 family orthologs of human IL‐17. Despite differences in their primary amino acid sequence, metatherian and prototherian IL‐17s share the same tertiary structure as human IL‐17s, suggesting similar functions. The analysis of available datasets for female fertility in therian mammals shows up‐regulation of IL‐17A and IL‐17D during placentation. IL‐17B and IL‐17D are also found to be over‐expressed in human fertility complication datasets, such as endometriosis or recurrent implantation failure. Conclusions: The conservation of the IL‐17 gene and protein across mammals suggests similar functions in all the analysed species. Despite significant differences, the upregulation of IL‐17 expression is associated with the establishment of pregnancy in eutherian and metatherian mammals. The dysregulation of IL‐17s in human reproductive disorders suggests them as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

γδ T cells are a subset of T cells that are characterized by the expression of a TCR‐γδ instead of a TCR‐αβ. Despite being outnumbered by their αβ T cell counterpart in many tissues, studies from the last 20 years underline their important and non‐redundant roles in tumor and metastasis development. However, whether a γδ T cell exerts pro‐ or antitumorigenic effects seems to depend on a variety of factors, many of them still incompletely understood today. In this review, we summarize mechanisms by which γδ T cells exert these seemingly contradictory effector functions in mice and humans. Furthermore, we discuss the current view on inducing and inhibiting factors of γδ T cells during cancer development. [ABSTRACT FROM AUTHOR]

Myeloid‐derived suppressor cells (MDSCs) hold promise for clinical applications due to their immunosuppressive properties, particularly in the context of inflammation. In the present study, the number and immunosuppressive activity of MDSCs isolated from naïve Il10−/−, Il17−/−, and WT mice as control, as well as from house dust mite extract (HDM)‐induced asthmatic Il10−/− and Il17−/− mice, were investigated. IL‐10 deficiency increased the number of polymorphonuclear (PMN)‐MDSCs in the lung, spleen, and bone marrow, without concurrent impairment of their suppressive activity in vitro. In the asthma model, the IL‐17 knockout was concomitant with a lower number and activity of monocytic (M)‐MDSCs and an altered inflammatory reaction with impaired lung function. Additionally, we found a higher baseline inflammation of the Il17−/− mice in the lung, manifested in increased airway resistance. We conclude that the impact of IL‐10 and IL‐17 deficiency on MDSCs differs in the context of inflammation. Accordingly, the in vitro experiments demonstrated an increased number of PMN‐MDSCs across tissues in Il10−/− mice, which indicates that IL‐10 might serve a pivotal role in preserving immune homeostasis under physiological circumstances. In the context of HDM‐induced airway inflammation, IL‐17 was found to be an important player in the suppression of pulmonary inflammation and regulation of M‐MDSCs. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to compare the levels of gingival crevicular fluid (GCF), salivary, and serum matrix metalloproteinase‐9, interleukin (IL)‐17, IL‐36γ, and IL‐38 in individuals with healthy periodontium, gingivitis, and periodontitis and to evaluate their correlations with clinical periodontal parameters. Materials and Methods: Ninety systemically healthy and nonsmoking volunteers divided into a healthy (H) group (n = 30), a gingivitis (G) group (n = 30), and a periodontitis (P) group (n = 30) were included in this study. Clinical periodontal parameters of volunteers were recorded, and GCF, unstimulated saliva, and serum samples were collected. Data analysis was done with enzyme‐linked immunosorbent assays. The Kruskal–Wallis test and Bonferroni correction were used for multiple comparisons and post hoc statistical analyses. Results: The group H had significantly lower clinical parameters than the group P (p < 0.001). GCF and salivary IL‐36γ and IL‐38 levels were significantly higher in the group P than in the H and G groups (p < 0.05). Positive correlations between biochemical findings and clinical periodontal parameters were observed. Conclusions: IL‐36γ and IL‐38 levels in GCF, saliva, and serum correlate with clinical periodontal parameters and may play a role in determining the activity of periodontitis. [ABSTRACT FROM AUTHOR]

Objective: To explore the role of interleukin (IL)‐17 in connective tissue disease‐associated pulmonary arterial hypertension (CTD‐PAH) and to investigate its possible mechanism on pulmonary artery smooth muscle cells (PASMCs). Methods: Enzyme‐linked immunosorbent assay (ELISA) were used to compare levels of serum IL‐17 in patients with CTD‐PAH and healthy controls (HCs). After treatment for 3 months, the serum IL‐17 levels were tested in CTD‐PAH. ELISA and immunohistochemistry were used to compare levels of serum IL‐17 and numbers of pulmonary artery IL‐17+ cells, respectively, in a rat model of monocrotaline‐induced PAH and untreated rats. Proliferation, migration, and inflammatory factors expression of PASMCs were assessed after stimulation with different concentrations of IL‐17 for various time periods. Proteins in the mitogen‐activated protein kinase (MAPK) pathway were examined by western blot. Results: Levels of IL‐17 were upregulated in patients with CTD‐PAH compared to HCs. After 3 months of treatment, serum IL‐17 levels were downregulated with pulmonary artery pressure amelioration. Moreover, serum IL‐17 levels and numbers of IL‐17+ cells infiltrating lung arterioles were increased in PAH model rats. IL‐17 could dose‐ and time‐dependently promote proliferation and migration of PASMCs as well as time‐dependently induce IL‐6 and intercellular cell adhesion molecule‐1 (ICAM‐1) expression. The levels of MKK6 increased after IL‐17 treatment. Inhibition of MAPK decreased proliferation of PASMCs. Conclusion: Levels of IL‐17 may increase in CTD‐PAH, and IL‐17 promotes proliferation, migration, and secretion of IL‐6 and ICAM in PASMCs, respectively, which likely involves the p‐38 MAPK pathway. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of therapeutic hypercapnia on the expression and function of gamma delta T (γδ T) cells during ischemia‐reperfusion injury (IRI) after lung transplantation. Methods: We randomly divided male Wistar rats into three groups (n = 6 in each group), the control group (group N), the IRI group (group I), and the therapeutic hypercapnia group (group H). We then assessed pulmonary edema, neutrophil infiltration, wet‐to‐dry (W/D) weight ratio, and microscopic histopathology and separately measured the levels of γδT cell surface antigen (TCR) and Interleukin‐17 (IL‐17) using flow cytometry and enzyme‐linked immunosorbent assays (ELISAs). Results: The infiltration of neutrophils and the expression of TCR and IL‐17 were significantly increased in the I group compared to the control, and the biopsy edema in group I was more severe. Arterial partial pressure of oxygen (PaO2) was decreased after reperfusion in group I compared with the control group. W/D weight ratio, neutrophil infiltration, and the expression of TCR and IL‐17 decreased drastically in the H group compared to the I group. Conclusion: Our findings suggest that γδ T lymphocytes were directly involved in lung injury. In addition, therapeutic hypercapnia effectively reduced the expression of γδ T cells and IL‐17, and this has the potential to become a treatment strategy for IRI and an intervention to improve lung function. [ABSTRACT FROM AUTHOR]

Diabetic foot ulcers (DFUs) are one of the most common and challenging complications of diabetes, yet our understanding of their pathogenesis remains limited. We collected gene expression data of DFU patients from public databases. Bioinformatics tools were applied for systematic analysis, including the identification of differentially expressed genes (DEGs), weighted gene co‐expression network analysis (WGCNA) and enrichment analysis. We further used single‐cell RNA sequencing to identify the distribution of different cell populations in DFU. Finally, key results were validated using reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR) and flow cytometry. We identified 217 DEGs between ulcerated and healthy skin, and 37 DEGs between healing ulcers and ulcers. WGCNA revealed that the cyan module had the highest positive correlation with healthy skin and negative correlation with ulcers. The black module had the highest negative correlation with healthy skin and positive correlation with ulcers. Enrichment analysis showed that the genes in the cyan module were mainly associated with complement and coagulation cascades, while the genes in the black module were mainly associated with the IL‐17 signalling pathway. In addition, CD8 T cells were significantly lower in ulcers than in healthy and healing ulcers. By comparing marker genes of CD8 T cells, we identified key genes in the cyan and black modules and validated their expression using RT‐qPCR. The proportion of CD8 T cells was increased in healing ulcers. Flow cytometry detected increased levels of CD8 T, B and natural killer cells in healing ulcers. CD8 T cells and related key genes play an important role in the healing process of DFU. The results of this study provide a new perspective for understanding the pathogenesis and treatment of DFU. [ABSTRACT FROM AUTHOR]

Dry eye (DE) is a multifactorial ocular surface disease characterised by an imbalance in tear homeostasis. The pathogenesis of DE is complex and related to environmental, immunological (e.g., T helper 17 cells) and other factors. However, the DE disease pathogenesis remains unclear, thereby affecting its clinical treatment. This study aimed to explore the mechanism through which prostaglandin E2 (PGE2) affects DE inflammation by regulating Th17. The DE mouse model was established through subcutaneous injection of scopolamine hydrobromide. The tear secretion test and break‐up time (BUT) method were used to detect tear secretion and tear film BUT, respectively. Enzyme‐linked immunosorbent assay (ELISA) was used to detect the concentrations of PGE2, interleukin (IL)‐17, IL‐6 and tumour necrosis factor (TNF‐α) in tear fluid and those of PGE2 and IL‐17 in the serum. RT‐qPCR and western blotting were used to test the mRNA and protein expression levels of IL‐17 and retinoid‐related orphan receptor‐γt (RORγt). PGE2 was highly expressed in the DE mouse model. The mRNA and protein levels of IL‐17 and the key Th17 transcription factor RORγt were increased in tissues of the DE mice. Moreover, PGE2 promoted tear secretion, reduced the BUT, increased the IL‐17 concentration in tears and increased the Th17 cell proportion in DE, whereas the PGE2 receptor inhibitor AH6809 reversed the effects of PGE2 on tear secretion, BUT, and the Th17 cell proportion in draining lymph node (DLN) cells. Taken together, the study findings indicate that PGE2 could induce DE‐related symptoms by promoting Th17 differentiation. [ABSTRACT FROM AUTHOR]

Aim: To investigate the relationship between interleukin‐17 (IL‐17), ferroptosis and osteogenic differentiation. Materials and Methods: We first analysed the changes in ferroptosis‐related molecules in experimental periodontitis models. The effects of erastin, a small‐molecule ferroptosis inducer, and IL‐17 on alveolar bone loss and repair in animal models were then investigated. Primary mouse mandibular osteoblasts were exposed to erastin and IL‐17 in vitro. Ferroptosis‐ and osteogenesis‐related genes and proteins were detected. Further, siRNA, immunofluorescence co‐localization and immunoprecipitation were used to confirm the roles of the nuclear factor erythroid‐2‐related factor 2 (NRF2) and phosphorylated signal transducer and activator of transcription 3 (p‐STAT3), as well as their interaction. Results: The levels of NRF2, glutathione peroxidase 4 and solute carrier family 7 member 11 were lower in the ligated tissues than in normal periodontal tissues. Alveolar bone loss in an in vivo experimental periodontitis model was aggravated by erastin and alleviated by IL‐17. In vitro, IL‐17 ameliorated erastin‐inhibited osteogenic differentiation by reversing ferroptosis. Altered NRF2 expression correlated with changes in ferroptosis‐related molecules and osteogenesis. Furthermore, the physical interaction between NRF2 and p‐STAT3 was confirmed in the nucleus. In IL‐17 + erastin‐stimulated osteoblasts, the p‐STAT3–NRF2 complex might actively participate in the downstream transcription of ferroptosis‐ and osteogenesis‐related genes. Conclusions: IL‐17 administration conferred resistance to erastin‐induced osteoblast ferroptosis and osteogenesis. The possible mechanism may involve p‐STAT3 directly interacting with NRF2. [ABSTRACT FROM AUTHOR]

Uric acid, an oxidation end‐product of purine metabolism, is reportedly to be a risk factor for kidney injury. However, its underlying mechanism is still a mystery. This study aimed to reveal the detailed roles of uric acid in inducing kidney injury and the possible mechanisms. Injection of rats with uric acid significantly increased tubular injury score, and levels of blood urea nitrogen, serum creatinine, and urine kidney injury molecule‐1. Uric acid increased the expression of collagen I, alpha‐smooth muscle actin, tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, and IL‐6. Kyoto Encyclopedia of Genes and Genomes analysis result showed the IL‐17 signaling pathway as the most significantly enriched pathway involved in hyperuricemia‐related kidney injury. Long‐term injection of uric acid induced significant production of IL‐17 and recruitment of Th17 cells. Treating rats with the anti‐IL‐17 mAb attenuated uric acid‐induced kidney injury, accompanied by the inactivation of nuclear factor‐κB (NF‐κB). In conclusion, uric acid was confirmed to be a risk factor for kidney injury via inducing IL‐17 expression. Neutralization of IL‐17 using the specific mAb relieved uric acid‐induced kidney injury via inhibition of NF‐κB signaling. Highlights: Uric acid induces kidney interstitial fibrosis and inflammation in rats.Uric acid induces IL‐17 expression.Anti‐IL‐17 mAb effectively inhibits uric acid‐induced kidney injury in rats.Anti‐IL‐17 mAb inhibited NF‐κB signaling in uric acid‐treated rats. [ABSTRACT FROM AUTHOR]

Interleukin (IL)‐23–independent IL‐17A production has been suggested to be involved in persistent manifestations of psoriatic disease, including anti–IL‐12/23–refractory psoriatic plaques; this study aimed to test this hypothesis by investigating the clinical and molecular effects of direct IL‐17A (with secukinumab) versus selective IL‐23 inhibition (with guselkumab) in patients with anti–IL‐12/23 (ustekinumab)–refractory psoriatic plaques. A 16‐week, randomized, open‐label, parallel‐group, Phase IIa study (ARROW, NCT03553823) was conducted in patients with ≥1 active psoriatic plaque (total clinical score [TCS] ≥6) at screening despite treatment with ustekinumab, and a Psoriasis Area and Severity Index (PASI) score 1–10. Patients were randomized 1:1 to receive secukinumab 300 mg (n = 20) or guselkumab 100 mg (n = 20). Biopsies from one refractory ('target plaque') were obtained at baseline and Week 16. The primary endpoint was the proportion of patients whose ustekinumab‐refractory target plaque achieved clear/almost clear status (TCS 0–2) at Week 16. Transcriptomic and histological analyses were conducted on target plaques to determine the molecular effects of direct IL‐17A versus selective IL‐23 inhibition. At Week 16, target plaque clear/almost clear status was achieved in 60.0% of patients treated with secukinumab versus 40.0% of patients treated with guselkumab (p = 0.1715). Molecular analyses identified that secukinumab modulated a greater proportion of psoriasis disease transcriptome genes (72.1% vs. 48.0%) and resulted in more histological responders (72.2% vs. 53.3%) compared with guselkumab. Secukinumab demonstrated a greater clinical and molecular effect on ustekinumab‐refractory psoriatic plaques versus guselkumab. These results are consistent with the hypothesis that IL‐23–independent IL‐17 mechanisms may be relevant to the inflammation driving refractory manifestations of psoriasis. [ABSTRACT FROM AUTHOR]

Objective: Recurrent pregnancy loss (RPL) and pre‐eclampsia (PE) are immune‐related pregnancy complications that have been linked to CD4+ T cells and their cytokines, which can be influenced by genetic polymorphisms. This meta‐analysis aimed to investigate the relationship between interleukin (IL)‐17 and ‐27 polymorphisms and the susceptibility to RPL and PE. Methods: All eligible case‐control studies published up to February 2023 were identified by searching PubMed, EMBASE, Cochrane, Web of Science, and Google Scholar. The risk of recurrent pregnancy loss and PE associated with the IL‐17 rs2275913, IL‐17 rs763780, IL‐27 rs153109, and IL‐27 rs17855750 polymorphisms were estimated for each study. Results: The meta‐analysis incorporated a total of 13 studies. The overall analysis indicated that IL‐17 rs2275913, IL‐17 rs763780, IL‐27 rs153109, and IL‐27 rs17855750 polymorphisms were not significantly associated with immune‐related pregnancy complications, including RPL and PE. However, when the analysis was stratified by disease type, the IL‐17 rs2275913 polymorphism was found to be associated with an increased risk of RPL (recessive model AA/GA + GG: OR = 1.68, 95% confidence interval [CI]: 1.13–2.49, p =.01). Conclusions: The IL‐17 rs763780, IL‐27 rs153109, and IL‐27 rs17855750 polymorphisms were not significantly associated with RPL and PE, whereas the IL‐17 rs2275913 polymorphism was associated with the susceptibility to recurrent miscarriage. [ABSTRACT FROM AUTHOR]

Citrinin, a mycotoxin produced by Penicillium citrinum and Penicillium verrucosum, mainly contaminates cereals. The aim of study was to investigate the novel immunoreactive effect of citrinin using a mouse model of psoriasis. A mouse model of psoriasis was generated by topical application of 5% imiquimod in female BALB/c mice. Standard rodent diet and rice samples with 3 ppm of citrinin were mixed to obtain a final citrinin concentration of 0.3 ppm, and a citrinin‐contaminated diet was fed to mice daily. Skin thickness, scratching behavior, and trans epidermal water loss (TEWL) were monitored continuously during the imiquimod application. Immediately after the final imiquimod application, ear skin and auricular lymph node (LN) were sampled for further analysis. Only a slight increase was observed in skin thickness in the citrinin exposure group; however, citrinin exposure significantly exacerbated hyperkeratinization and inflammatory cell infiltration in histological evaluation. TEWL, which is representative of cutaneous barrier function, was significantly increased by citrinin exposure. In terms of immune function, the number of immune cells in LN (T cells and dendritic cells) and gene expression of interleukin (IL)‐17 in skin tissue were significantly increased by citrinin exposure. Direct interaction of dendritic cells (DCs) in citrinin‐induced psoriasis development was further examined by proinflammatory cytokine determination in THP‐1 cells and murine bone marrow derived DCs. IL‐6 and/or tumor necrosis factor α were significantly increased by citrinin exposure. Taken together, our results imply that oral exposure to citrinin exacerbates the symptoms of a mouse model of psoriasis via direct activation of DCs. The aim of study was to investigate the novel immunoreactive effect of citrinin, a mycotoxin produced by Penicillium citrinum and P. verrucosum, using a mouse model of psoriasis. A citrinin‐contaminated diet (0.3 ppm) was fed to a mouse model of psoriasis daily, and skin thickness, scratching behavior, TEWL, and immune functions were monitored. Our results imply that oral exposure to citrinin exacerbates the symptoms of a mouse model of psoriasis via direct activation of dendritic cells. [ABSTRACT FROM AUTHOR]

Objective: Chronic spontaneous urticaria (CSU) has a profound impact on the sleep quality, productivity and overall quality of life of affected individuals. This study aimed to investigate the correlation between serum Th17/Treg immune dysregulation and the severity of CSU in patients. Methods: Clinical baseline data of 120 CSU patients and matched healthy controls were recorded. The pruritus level, disease severity, and quality of life of CSU patients were assessed using the visual analogue scale, weekly Urticaria Activity Score and chronic urticaria quality of life questionnaire, respectively. The Th17/Treg cell ratio was detected by flow cytometry. ELISA was used to measure the levels of serum Th17 cytokines (IL‐17, IL‐21) and Treg cytokines (TGF‐β1, IL‐35). Pearson's correlation analysis was conducted to examine the associations between these indicators. Results: No significant differences were identified in terms of sex, age, and BMI between the two groups. However, CSU patients exhibited a significant increase in the Th17 cell ratio, as well as the elevated serum levels of TGF‐β1, IL‐17 and, IL‐21. Conversely, the proportion of Treg cells and the levels of IL‐35 were remarkably decreased in CSU patients. Peripheral blood Th17 cells were negatively correlated with Treg cells. The severity of pruritus, life quality, and disease severity in CSU patients were positively correlated to Th17 cell ratio, and inversely correlated with Treg cell proportion. Conclusions: A positive correlation was found between the percentage of peripheral blood Th17 cell in CSU patients and the pruritus level, life quality, and disease severity. In constrast, there was a negative correlation between the proportion of peripheral blood Treg cells and these clinical parameters. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion Bronchial asthma (BA) is a heterogeneous disease characterized by chronic airway inflammation. This study investigated the serum miR‐27a‐3p/activating transcription factor 3 (ATF3) expression in children with BA and their correlations with airway inflammation.Children with BA (N = 120) and healthy children (N = 108) were enrolled. Serum levels of interleukin (IL)‐17, IL‐6, tumor necrosis factor (TNF)‐α, immunoglobulin E (IgE), miR‐27a‐3p, ATF3, and the number of eosinophils (EOS) were measured using enzyme‐linked immunosorbent assay (ELISA), reverse transcription quantitative polymerase chain reaction (RT‐qPCR), and an automatic hematology analyzer. The correlations between miR‐27a‐3p and ATF3 and between miR‐27a‐3p/ATF3 and inflammation‐related factors were analyzed by the Pearson method. The diagnostic values of miR‐27a‐3p and ATF3 in BA were evaluated using receiver operating characteristic (ROC) curves. The influencing factors of BA were assessed using multivariate logistic regression. Finally, the targeting relation between miR‐27a‐3p and ATF3 was predicted and analyzed by TargetScan and Starbase databases, and dual‐luciferase assay.There were significant differences in forced expiratory volume in 1 s (FEV1)% predicted and FEV1/forced vital capacity (FVC)%, serum levels of IgE, IL‐17, IL‐6, and TNF‐α, and EOS numbers between healthy children and BA children. Serum miR‐27a‐3p was negatively correlated with ATF3 and positively correlated with inflammation‐related factors in BA children. Serum ATF3 mRNA levels were negatively correlated with inflammatory factors in BA children. miR‐27a‐3p and ATF3 had good diagnostic values in BA children. FEV% predicted, IL‐6, TNF‐α, miR‐27a‐3p, and ATF3 were independent risk factors for BA. miR‐27a‐3p targeted ATF3.Serum miR‐27a‐3p was highly expressed, whereas ATF3 was poorly expressed in BA children, and they were significantly correlated with airway inflammation, had good diagnostic values in BA children, and were independent risk factors for asthma. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the biliary tree and a risk factor for development of cholangiocarcinoma (CCA). The pathogenesis of PSC‐related CCA is largely unclear, although it is assumed that chronic inflammatory environment plays a pivotal role. We aimed to investigate the effect of inflammation‐related cytokines in PSC on the proliferation rate of cancer cells. For this, the proliferation index in PSC‐CCA and sporadic CCA was determined by Ki‐67 immunohistochemistry. The percentage of Ki‐67 positivity in cancer cells was significantly higher in PSC‐CCA than in sporadic CCA (41.3% ± 5.7% vs 25.8% ± 4.1%; P =.038). To assess which cytokines in the inflammatory environment have the potential to stimulate cancer cell proliferation, patient‐derived CCA organoids (CCAOs) were exposed to five cytokines related to PSC (Interleukin (IL)‐1β, IL‐6, IL‐17A, interferon gamma and tumor necrosis factor alpha). Only IL‐17A showed a significant stimulatory effect on cell proliferation in CCAOs, increasing organoid size by 45.9% ± 16.4% (P <.01) and proliferation rate by 38% ± 16% (P <.05). IL‐17A immunohistochemistry demonstrated that PSC‐CCA might express more IL‐17A than sporadic CCA. Moreover, correlation analysis in sporadic CCA and PSC‐CCA found a significant correlation between IL‐17A expression and proliferation. In conclusion, tumor cell proliferation is increased in PSC‐CCA cells compared with sporadic CCA cells. IL‐17A increases CCA cell proliferation in vitro and may contribute to the high proliferation rate in PSC‐CCA in situ. Therefore, IL‐17A represents a new potential therapeutic target in (PSC‐)CCA, to be tested in future trials. [ABSTRACT FROM AUTHOR]

Lichen planus is a chronic T‐cell‐mediated disorder in which lymphocytes, including Th17 cells, react toward the dermo‐epidermal junction, which shows interface changes. Recently, IL‐17‐mediated changes in the oral mycobiome, including the proliferation of Candida and Aspergillus fungi, have been proposed as a possible pathomechanism of oral lichen planus (OLP). We treated a 54‐year‐old male who had been suffering from psoriatic arthritis. Secukinumab rapidly improved the skin and joint symptoms, but a painful erosion on the lip and thrush on the buccal mucosa appeared within 4 weeks. The erosion was histopathologically diagnosed as OLP. Although the candidiasis was successfully treated with topical miconazole nitrate, the labial OLP worsened during the secukinumab administration, despite the application of various topical agents. We finally switched from secukinumab to risankizumab, an anti‐IL‐23p19 agent, which dramatically improved the patient's OLP lesion in 4 weeks without candidiasis recurrence. Anti‐IL‐23p19 agents do not affect the oral mycobiome, and they are a potential therapeutic option for refractory OLP, including OLP induced by biologics. [ABSTRACT FROM AUTHOR]

Aim: The progression of atherosclerosis can lead to the occurrence of multiple cardiovascular diseases (coronary heart disease, etc.). E prostanoid receptor‐3 (EP3) is known to participate in the progression of atherosclerosis. This study aimed to investigate the mechanism by which EP3 modulates the development of atherosclerosis. Methods and results: ApoE−/− mice were used to construct in vivo model of atherosclerosis. Human aortic smooth muscle cells (HASMCs) were stimulated with oxidized low‐density lipoprotein (ox‐LDL) to construct in vitro model of atherosclerosis. mRNA expressions were assessed by qRT‐PCR, and western blot was applied to assess the protein levels. CCK‐8 assay was applied to assess the cell viability. The inflammatory cytokines levels were assessed by enzyme‐linked immunosorbent assay, and flow cytometry was applied to assess cell apoptosis. In vivo experiment was constructed to investigate the impact of EP3 in atherosclerosis development. L‐798106 (EP3 inhibitor) significantly inhibited the levels of pro‐inflammatory cytokines in atherosclerosis in vivo. EP3 inhibitor (L‐798106) significantly reversed ox‐LDL‐caused HASMCs injury via inhibiting the apoptosis and inflammatory responses (P < 0.05). The levels of interleukin‐17 (IL‐17) and intercellular adhesion molecule‐1 (ICAM‐1) in HASMCs were elevated by ox‐LDL, whereas L‐798106 or knockdown of cyclic AMP (cAMP) response element‐binding protein (CREB) notably restored this phenomenon (P < 0.05). EP3 overexpression further aggravated ox‐LDL‐induced inflammation in HASMCs, and EP3 up‐regulated the levels of IL‐17 and ICAM‐1 in ox‐LDL‐treated HASMCs (P < 0.05). EP3 up‐regulation promoted the inflammatory responses in ox‐LDL‐treated HASMCs through mediation of cAMP/protein kinase A (PKA)/CREB/IL‐17/ICAM‐1 axis (P < 0.05). Conclusions: EP3 inhibitor alleviates ox‐LDL‐induced HASMC inflammation via mediation of cAMP/PKA/CREB/IL‐17/ICAM‐1 axis. Our study might shed new lights on discovering novel strategies against atherosclerosis. [ABSTRACT FROM AUTHOR]

We previously reported that regulatory T (Treg) cells expressing CTLA‐4 on the cell surface are abundant in head and neck squamous cell carcinoma (HNSCC). The role of expanded Treg cells in the tumor microenvironment of HNSCC remains unclear. In this study, we reveal that the tumor microenvironment of HNSCC is characterized by the high expression of genes related to Treg cells, dendritic cells (DCs), and interleukin (IL)‐17‐related molecules. Increased expression of IL17A, IL17F, or IL23A contributes to a favorable prognosis of HNSCC. In the tumor microenvironment of HNSCC, IL23A and IL12B are expressed in mature dendritic cells enriched in regulatory molecules (mregDCs). The mregDCs in HNSCC are a migratory and mature phenotype; their signature genes strongly correlate with Treg signature genes in HNSCC. We also observed that IL17A was highly expressed in Th17 cells and exhausted CD8+ T cells in HNSCC. These data suggest that mregDCs in HNSCC may contribute to the prognosis by balancing Treg cells and effector T cells that produce IL‐17. Targeting mregDCs may be a novel strategy for developing new immune therapies against HNSCC. [ABSTRACT FROM AUTHOR]

Background: Emerging research suggests that local lymphatic tissue such as tonsils have important role in regulating the immune responses. However, allergen sensitization‐induced alterations in transcriptome of tonsils are not known. Objectives: To examine the key differences in tonsillar gene expression between atopic and non‐atopic subjects and further by type of sensitization. Methods: RNA‐sequencing was performed on 52 tonsillar samples from atopic and non‐atopic tonsillectomy patients. Sensitization to common food‐ and aero‐allergen was defined by allergen specific IgE. Following groups were studied: (1) aero‐ and food‐allergen sensitized (AS+FS) versus non‐sensitized (NS), (2) aeroallergen‐sensitized (AS) versus food‐allergen sensitized (FS), (3) AS versus NS, (4) FS versus NS. Bioinformatics analysis was done using DESeq2(v3.10.2), WGCNA and GATK pipeline in R software (v3.3.1). Protein–protein interaction network was made from String database. Results: We studied 13 aeroallergen‐sensitized, 6 food‐allergen sensitized, 4 both food‐and aero‐allergen‐sensitized and 29 non‐sensitized tonsillectomy patients. Overall, 697 unique differentially expressed genes (DEGs) were detected in all sensitized subgroups including chemokines (CXCL2, CXCL8, CXCL10, CXCL11), IL‐20RA, MUC1 and MUC20. When comparing different groups, the gene expression profiles overlapped except the AS versus FS group comparison, suggesting significantly different gene expression between the two sensitization subgroups. Furthermore, aeroallergen‐sensitized subjects had more prominent immune responses compared with non‐sensitized and food‐allergen sensitized subjects including gene expression for IL‐17 pathway and Toll‐like receptor signalling pathway. Conclusion: Allergic sensitization is associated with extensive tonsillar transcriptomic alterations and changes in immune related genes and pathways. Distinct differences were found between aero‐allergen and food‐allergen sensitization. [ABSTRACT FROM AUTHOR]

Rituximab and prednisone are commonly used treatments for autoimmune hemolytic anemia (AIHA), where the body's immune system attacks and destroys its red blood cells. However, some AIHA patients may become refractory to rituximab treatment, and this can result in continued hemolysis and persistent anemia, making it challenging for affected individuals to manage their symptoms. The underlying causes of rituximab refractoriness in AIHA patients can be complex and vary from patient to patient. Herein, we present a case of newly diagnosed warm and cold AIHA that remained in remission with an interleukin‐23 inhibitor. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection can cause coronavirus disease 2019 (COVID‐19), an acute respiratory inflammation that has emerged worldwide since December 2019, and it quickly became a global epidemic. Inflammatory bowel disease (IBD) is a group of chronic nonspecific intestinal inflammatory diseases whose etiology has not been elucidated. The two have many overlapping symptoms in clinical presentation, such as abdominal pain, diarrhea, pneumonia, etc. Imbalance of the autoimmune system in IBD patients and long‐term use of immunosuppressive drugs may increase the risk of infection; and systemic symptoms caused by COVID‐19 may also induce or exacerbate intestinal inflammation. It has been found that the SARS‐CoV‐2 receptor angiotensin converting enzyme 2, which is highly expressed in the lung and intestine, is an inflammatory protective factor, and is downregulated and upregulated in COVID‐19 and IBD, respectively, suggesting that there may be a coregulatory pathway. In addition, the immune activation pattern of COVID‐19 and the cytokine storm in the inflammatory response have similar roles in IBD, indicating that the two diseases may influence each other. Therefore, this review aimed to address the following research questions: whether SARS‐CoV‐2 infection leads to the progression of IBD; whether IBD increases the risk of COVID‐19 infection and poor prognosis; possible common mechanisms and genetic cross‐linking between the two diseases; new treatment and care strategies for IBD patients, and the feasibility and risk of vaccination in the context of the COVID‐19 epidemic. [ABSTRACT FROM AUTHOR]

Secukinumab demonstrated high efficacy and favorable safety profile in patients with moderate‐to‐severe plaque psoriasis (PsO) in clinical trials. However, understanding of patient characteristics and clinical outcomes in real world in Thailand is still limited. To describe patient characteristics, effectiveness and safety of secukinumab in Thai PsO patients. This retrospective study analyzed data from medical records of adult PsO patients who initiated secukinumab at 7 dermatology centers from September 2017 to April 2021. Study outcomes included patient characteristics and changes in Psoriasis Area and Severity Index (PASI) score from baseline at weeks 4 and 16 after secukinumab initiation. Adverse events were recorded. Subgroup analyses by adherence rate and completeness of loading dose were performed. Of 163 patients, the mean (SD) age was 44.0 (14.0) years. Most patients (84.7%) were previously treated with topical therapy while 62.0% and 21.5% of patients had received systemic and biologic therapy, respectively. The mean baseline PASI score was 15.4 (9.3). Overall, the mean PASI score improved by 58.0% at week 4 and 78.4% at week 16. Statistically significant differences in PASI approvement were revealed among subgroups of patients with different loading dose and adherence rate. Adverse effects were reported in 8.0% of patients. The characteristics of patients in this study were slightly different from clinical trials in terms of demographic and clinical characteristics, as well as PsO treatment. Secukinumab was effective and safe in Thai patients with PsO, especially among those with complete loading dose and a higher adherence rate. [ABSTRACT FROM AUTHOR]

Background: Psoriasis (PsO) is a systemic autoimmune disease. Many pro‐inflammatory and anti‐inflammatory biomarkers have been associated with the pathogenetic process of psoriasis. IL‐35 act as an anti‐inflammatory cytokine through downregulation of TH‐17 cell development and cytokine production. So, IL‐35 might be utilized as potential future therapeutic agent for psoriasis. Aims: To investigate the association between inflammatory (IL‐17, TNF‐α, IFN‐γ) and anti‐inflammatory cytokines (IL‐35, TGF‐β) in psoriasis patients. Patients and Methods: A case–control study enrolled two groups: (Group I: 40 patients with psoriasis) and (Group II: 40 healthy age and sex‐matched subjects). Full history was taken from all cases along with full dermatologic examination. The assessment of psoriasis severity was conducted by using PASI score. Assessment of inflammatory (IL‐17, TNF‐α, IFN‐γ) and anti‐inflammatory cytokines (IL‐35, TGF‐β) was performed by using ELISA technique. Results: There was a statistically significant increase of mean level of TNF‐α, IL‐17, and IFN‐γ among psoriasis cases in comparison with controls. The mean level of TGF‐β and IL‐35 was statistically significantly reduced among the psoriasis cases in comparison with controls. TNF‐α, IL‐17, and IFN‐γ showed a significant strong positive association in between and statistically significant strong negative relationship with IL‐35 and TGF‐β. Conclusion: IL‐35 has a significant role in the pathogenetic process of PsO, and it serves as a potential future therapeutic agent for psoriasis. The current results could be used as a clue for the utilization of inflammatory (IL‐17, TNF‐α, IFN‐γ) versus anti‐inflammatory cytokines (IL‐35, TGF‐β) in psoriasis patients as a diagnostic biomarker for severity of cases with psoriasis. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disorder with significant morbidity and impairment of life quality. Prevalence is increasing around the world; therefore, intensive research is ongoing to understand the mechanisms of development of AD and offer new treatment options for AD patients. Aims: To investigate the association between Inflammatory (IL‐17, TNF‐α, IFN‐γ) versus anti‐Inflammatory Cytokines (IL‐35, TGF‐β) in AD patients. Patients and Methods: A case control study included 40 AD patients and 20 age‐ and sex‐matched healthy subjects. Cases were subjected to full history taking and full dermatological examination. The assessment of disease severity was conducted by using SCORAD score. Assessment of inflammatory (IL‐17, TNF‐α, IFN‐γ) and anti‐Inflammatory Cytokines (IL‐35, TGF‐β) was performed by using ELISA technique. Results: The mean level of TNF‐α, IL‐17 was statistically significantly higher in the AD cases as compared with the control group. The mean level of TGF‐β, Il‐35, and IFN‐γ was statistically significantly lower in the Atopic dermatitis cases as compared with the control group. There was statistically significant strong positive correlation between TNF‐α with SCORAD score and IL‐17 while there was statistically significant strong negative correlation between TNF‐α with TGF‐β and IL‐35. There was statistically significant strong positive correlation between IL‐17 with SCORAD score and TNF‐α while there was statistically significant strong negative correlation between IL‐17 with TGF‐β and IL‐35. Conclusion: The current results could be used as a clue for the utilization of inflammatory (IL‐17, TNF‐α, IFN‐γ) versus anti‐inflammatory Cytokines (IL‐35, TGF‐β) in AD as a diagnostic biomarker for severity of cases with Atopic dermatitis. IL‐17 plays an important role in the pathogenesis of AD, and IL‐17 blocker may be used as a potential future treatment of AD. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic, inflammatory skin disease in which the interleukin (IL)-23/IL-17 axis plays a central role. Bimekizumab is a novel antibody that targets both IL-17A and IL-17F. This retrospective study aimed to assess the long-term effectiveness and safety of 52-week treatment with bimekizumab, and to identify predictive factors for short- (16 weeks) and long-term (52 weeks) responders (i.e., achievers of a Psoriasis Area and Severity Index (PASI) score of 100) to bimekizumab in Japanese patients with psoriasis. The study was conducted on 56 Japanese patients (aged ≥ 15 years) with moderate-to-severe psoriasis treated with bimekizumab from May 2022 to March 2024. The therapeutic effectiveness was evaluated by the transition of PASI scores during treatment. Baseline characteristics and clinical and laboratory indexes were compared between responders and poor responders. Treatment-emergent adverse events (TEAEs) were recorded to assess the safety of the treatment. At week 52, the achievement of PASI 100, static Physician's Global Assessment 0/1, and the Dermatology Life Quality Index 0/1 were 72.4%, 94.7%, and 93.3%, respectively. Short-term responders showed lower baseline values of neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio (MLR), and systemic inflammatory response index compared to poor responders. Long-term responders showed younger age and lower MLR compared to poor responders. TEAEs were mild or moderate, without serious adverse events. Long-term treatment with bimekizumab is effective and safe for psoriasis patients. Lower MLR and younger age might predict long-term response to treatment with bimekizumab, aiding in personalized treatment strategies., (© 2024 Japanese Dermatological Association.)

Most individuals infected with Mycobacterium tuberculosis (Mtb) have latent tuberculosis (TB), which can be diagnosed with tests (such as the QuantiFERON‐TB Gold test [QFT]) that detect the production of IFN‐γ by memory T cells in response to the Mtb‐specific antigens 6 kDa early secretory antigenic target EsxA (Rv3875) (ESAT‐6), 10 kDa culture filtrate antigen EsxB (Rv3874) (CFP‐10), and Mtb antigen of 7.7 kDa (Rv2654c) (TB7.7). However, the immunological mechanisms that determine if an individual will develop latent or active TB remain incompletely understood. Here we compared the response of innate and adaptive peripheral blood lymphocytes from healthy individuals without Mtb infection (QFT negative) and from individuals with latent (QFT positive) or active TB infection, to determine the characteristics of these cells that correlate with each condition. In active TB patients, the levels of IFN‐γ that were produced in response to Mtb‐specific antigens had high positive correlations with IL‐1β, TNF‐α, MCP‐1, IL‐6, IL‐12p70, and IL‐23, while the proinflammatory cytokines had high positive correlations between themselves and with IL‐12p70 and IL‐23. These correlations were not observed in QFT‐negative or QFT‐positive healthy volunteers. Activation with Mtb‐soluble extract (a mixture of Mtb antigens and pathogen‐associated molecular patterns [PAMPs]) increased the percentage of IFN‐γ–/IL‐17–producing NK cells and of IL‐17–producing innate lymphoid cell 3 (ILC3) in the peripheral blood of active TB patients, but not of QFT‐negative or QFT‐positive healthy volunteers. Thus, active TB patients have both adaptive and innate lymphocyte subsets that produce characteristic cytokine profiles in response to Mtb‐specific antigens or PAMPs. These profiles are not observed in uninfected individuals or in individuals with latent TB, suggesting that they are a response to active TB infection. [ABSTRACT FROM AUTHOR]

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a poorly understood disease. Accumulating evidence suggests that autoimmune dysfunction is involved in the development of CP/CPPS. Interleukin‐17 (IL‐17) is associated with the occurrence and development of several chronic autoimmune inflammatory diseases. However, the molecular mechanisms underlying the role of IL‐17 in CP/CPPS are not clear. We confirmed that IL‐17 was increased in the prostate tissues of experimental autoimmune prostatitis (EAP) mice. Corresponding to the increase of IL‐17, neutrophil infiltration and the levels of CXCL1 and CXCL2 (CXC chemokine ligands 1 and 2) were also increased in the prostate of EAP. Treatment of EAP mice with an IL‐17‐neutralizing monoclonal antibody (mAb) decreased the number of infiltrated neutrophils and CXCL1 and CXCL2 levels. Depletion of neutrophils using anti‐Ly6G antibodies ameliorated the inflammatory changes and hyperalgesia caused by EAP. Fucoidan, a could potent inhibitor of neutrophil migration, also ameliorate the manifestations of EAP. Our findings suggested that IL‐17 promoted the production of CXCL1 and CXCL2, which triggered neutrophil chemotaxis to prostate tissues. Fucoidan might be a potential drug for the treatment of EAP via the effective inhibition of neutrophil infiltration. [ABSTRACT FROM AUTHOR]

Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare type of epidermal nevus, commonly arising in childhood. We present a case of a 13‐year‐old female with Blaschkoid psoriasiform plaques extending from her left foot to the scalp, sparing the right side of the body. While treatment options historically show variable success, we trialed an IL‐17a receptor inhibitor as studies have shown increased levels of IL‐17 receptor expression in ILVEN keratinocytes. At both 3 and 6 months after treatment initiation there was found to be significant improvement. We propose brodalumab as an effective treatment option for widespread ILVEN. [ABSTRACT FROM AUTHOR]

Human breast milk (HBM) effectively prevents and cures neonatal bronchopulmonary dysplasia (BPD). Exosomes are abundant in breast milk, but the function of HBM‐derived exosomes (HBM‐Exo) in BPD is still unclear. This study was to investigate the role and mechanism of HBM‐Exo in BPD. Overall lung tissue photography and H&E staining showed that HBM‐Exo improved the lung tissue structure collapse, alveolar structure disorder, alveolar septum width, alveolar number reduction and other injuries caused by high oxygen exposure. Immunohistochemical results showed that HBM‐Exo improved the inhibition of cell proliferation and increased apoptosis caused by hyperoxia. qPCR and Western blot results also showed that HBM‐Exo improved the expression of Type II alveolar epithelium (AT II) surface marker SPC. In vivo study, CCK8 and flow cytometry showed that HBM‐Exo improved the proliferation inhibition and apoptosis of AT II cells induced by hyperoxia, qPCR and immunofluorescence also showed that HBM‐Exo improved the down‐regulation of SPC. Further RNA‐Seq results in AT II cells showed that a total of 88 genes were significantly different between the hyperoxia and HBM‐Exo with hyperoxia groups, including 24 up‐regulated genes and 64 down‐regulated genes. KEGG pathway analysis showed the enrichment of IL‐17 signalling pathway was the most significant. Further rescue experiments showed that HBM‐Exo improved AT II cell damage induced by hyperoxia through inhibiting downstream of IL‐17 signalling pathway (FADD), which may be an important mechanism of HBM‐Exo in the prevention and treatment of BPD. This study may provide new approach in the treatment of BPD. [ABSTRACT FROM AUTHOR]

Objectives: This study investigates the effects and mechanisms of intestinal microbiota transplantation on cerebral ischemia reperfusion injury in aged mice. Methods: We constructed a middle cerebral artery occlusion model after fecal microbiota transplantation from young C57 mice to aged C57 mice for 30 consecutive days via enema. The neurological deficit score, cerebral infarction volume, fecal flora composition, and IL‐17 levels in the colon, brain, and serum were evaluated in young mice, aged mice, and aged mice that received fecal microbiota transplantation. Moreover, we administered rIL‐17A through caudal vein injection to verify its effect on cerebral ischemia reperfusion injury in aged mice. Results: We find that aged mice exhibited larger cerebral infarction volume and more severe neurological deficit than young mice after middle cerebral artery occlusion. Bacteroidetes increased and firmicutes decreased significantly in the feces of aged mice after microbiota transplantation. Furthermore, the transplanted mice showed improved neurological function and reduced infarction volume after middle cerebral artery occlusion compared with the control aged mice. We also find that the neuroprotective effect of the microbiota transplantation was reversed by pre‐treatment of rIL‐17A. Conclusion: In summary, intestinal microbiota transplantation can alleviate cerebral ischemia reperfusion injury in aged mice by restoring their microbiota environment and inhibiting IL‐17 in the gut, serum, and brain tissue. [ABSTRACT FROM AUTHOR]

Ability of IL‐17‐producing CD8+ T cells (Tc17) to transform into cytotoxic anti‐tumour effectors makes them a promising candidate for immune effector cell (IEC) therapy. However, key factors regulating Tc17 reprogramming remain poorly defined, hindering translation of Tc17‐based IEC use from bench to bedside. We probed the effects of multiple cytokines and underlying signalling pathways on Tc17 cells and identified pivotal role for IL‐4 and PI3K/AKT in promoting Tc17 transformation into cytotoxic IFN‐γ‐producing IECs, an effect dependent on Eomes expression. IL‐4 not only triggered Tc17 cytotoxicity, but also induced cell expansion, which significantly improved the antitumour potential of Tc17 cells compared to that of IFN‐γ‐producing CD8+ T cells (Tc1) in a murine model. Furthermore, IL‐4/AKT signalling drove the upregulation of the T‐cell receptor‐associated transmembrane adaptor 1 (Trat1) in Tc17 cells to promote IL‐4‐induced T‐cell receptor stabilization and Tc17 cytotoxicity. Finally, we proposed a possible procedure to expand human Tc17 from peripheral blood of cancer patients, and confirmed the function of IL‐4 in Tc17 reprogramming. Collectively, these results document a novel IL‐4/AKT/Eomes/Trat1 axis that promotes expansion and transformation of Tc17 cells into cytotoxic effectors with a therapeutic potential. IL‐4 priming of Tc17 cells should be further explored as a cell therapy engineering strategy to generate IECs to augment anti‐tumour responses. [ABSTRACT FROM AUTHOR]

Objectives: The contribution of adaptive vs. innate lymphocytes to IL‐17A and IL‐22 secretion at the end stage of chronic lung diseases remains largely unexplored. In order to uncover tissue‐ and disease‐specific secretion patterns, we compared production patterns of IL‐17A and IL‐22 in three different human end‐stage lung disease entities. Methods: Production of IL‐17A, IL‐22 and associated cytokines was assessed in supernatants of re‐stimulated lymphocytes by multiplex assays and multicolour flow cytometry of conventional T cells, iNKT cells, γδ T cells and innate lymphoid cells in bronchial lymph node and lung tissue from patients with emphysema (n = 19), idiopathic pulmonary fibrosis (n = 14) and cystic fibrosis (n = 23), as well as lung donors (n = 17). Results: We detected secretion of IL‐17A and IL‐22 by CD4+ T cells, CD8+ T cells, innate lymphoid cells, γδ T cells and iNKT cells in all end‐stage lung disease entities. Our analyses revealed disease‐specific contributions of individual lymphocyte subpopulations to cytokine secretion patterns. We furthermore found the high levels of microbial detection in CF samples to associate with a more pronounced IL‐17A signature upon antigen‐specific and unspecific re‐stimulation compared to other disease entities and lung donors. Conclusion: Our results show that both adaptive and innate lymphocyte populations contribute to IL‐17A‐dependent pathologies in different end‐stage lung disease entities, where they establish an IL‐17A‐rich microenvironment. Microbial colonisation patterns and cytokine secretion upon microbial re‐stimulation suggest that pathogens drive IL‐17A secretion patterns in end‐stage lung disease. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection can generate a systemic inflammatory response, characterized by a cytokine storm and associated with an exaggerated release of proinflammatory cytokines, including tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), and IL‐17, all of which can affect the liver. Here, we aimed to evaluate the cytokine profiles of patients suffering from coronavirus disease (COVID)‐19 and/or hepatitis. We subjected 87 patients to serology and/or polymerase chain reaction analysis for the hepatitis C virus. They were also tested for TNF‐α, IL‐6, and IL‐17 using commercial immunoassay kits. The test results of the COVID‐19/hepatitis C patients (n = 8) were compared with that of the negative controls (n = 28), hepatitis C patients (n = 29), and COVID‐19 patients (n = 22). All COVID‐19 patients (mono‐ and coinfected) expressed high levels of cytokines. The COVID‐19/hepatitis patients exhibited higher levels of IL‐6 (6.33 ± 3.9 pg/ml) and IL‐17 (102.23 ± 2.7 pg/ml); however, TNF‐α values were lower (68.08 ± 15.88 pg/ml), as compared with that of the hepatitis patients (p < 0.001), and lower than that of the COVID‐19 patients and exceptionally for TNF‐α (p < 0.05). These data highlight the importance of monitoring patients with hepatitis and COVID‐19. Highlights: A significant increase in the serological levels of IL‐6, IL‐17, and interesting results of TNF‐α in the SARS‐CoV‐2‐infected patients were found.Coinfection with HCV and SARS‐CoV‐2 needs to be more investigated and can help to elucidate the relevant aspects of the inflammatory process that is necessary for monitoring post‐COVID affections in patients with previous liver disorders. [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration (IDD) serves as an independent risk factor for lower back pain and is closely associated with spinal musculoskeletal disorders, including lumbar disc herniation, radiculopathy, and myelopathy. Interleukin‐17 (IL‐17), also named IL‐17A, is a critical signature cytokine of T‐helper 17 cells. Upon binding to the IL‐17 receptor A/C heterodimeric complex, IL‐17 can trigger multiple signal transduction pathways to stimulate gene transcription and increase messenger RNA stability. IL‐17 expression is significantly increased in degenerative disc tissue and shows a positive correlation with disease severity. IL‐17 has been shown to accelerate the development of IDD by promoting extracellular matrix degradation, enhancing inflammatory response, inducing neoangiogenesis, and inhibiting nucleus pulposus cell autophagy and proliferation. Targeting IL‐17 represents a novel and promising approach for the therapeutic intervention of IDD. In this review, we summarized the recent progression about the role of IL‐17 in IDD and highlighted its therapeutic implications. [ABSTRACT FROM AUTHOR]

Background: Rosacea is a chronic inflammatory skin disease characterized with increased serum and tissue inflammatory mediators. IL‐17 is a well‐known inflammatory mediator that plays important roles in pathogenesis of inflammatory skin diseases. Previous studies reported that Th17 pathway is activated in rosacea and IL‐17, one of Th17 signature cytokines, is elevated in tissue samples of rosacea patients. Objectives: The aim of this study was to investigate serum IL‐17 levels in rosacea patients and to study its relationship with disease characteristics. Methods: Sixty patients diagnosed with rosacea and 60 healthy controls were included in the study. Serum IL‐17 concentrations were measured using enzyme‐linked immunosorbent assay (ELISA). Results: The mean serum IL‐17 level was 8.03 pg/mL (SD = 1.47) in rosacea patients and 7.37 pg/mL (Sd = 1.19) in controls. Serum IL‐17 levels were significantly higher in rosacea (p = 0.002). Serum IL‐17 levels were similar among patients with erythematotelangiectatic (ET) and papulopustular (PP) rosacea (8.02 vs 8.06, p = 0.83). Serum IL‐17 levels did not correlate with rosacea severity (p = 0.59, r = 0.07 in ET rosacea; p = 0.88, r = 0.02 in PP rosacea), age of onset (p = 0.58, r = −0.07), and disease duration (p = 0.37, r = −0.11). Primary features and global assessments did not correlate with serum IL‐17 levels (all p > 0.05). Among secondary features, edema showed a significant negative correlation with serum IL‐17 concentrations (p = 0.037, r = −0.26). Conclusions: Our study showed increased serum IL‐17 levels in rosacea patients and a significant correlation between IL‐17 concentrations and secondary features of the disease suggesting IL‐17 may contribute to pathogenesis of rosacea and may be a new target for rosacea treatment. [ABSTRACT FROM AUTHOR]

Tissue‐resident memory γδT cells at mucosal and epithelial sites play an important role for pathogen clearance, immunosurveillance, and participating in physiological processes. Different from other barrier sites, the immune cells in uterus face the protection against infections and tolerate an allogeneic fetus during a successful pregnancy. In the previous study, we found that tissue‐resident memory γδT cells were enriched both in human and murine uterus and highly expressed IL‐17 that promoted the invasion of trophocytes in vitro. In the current study, we found that γδT cells in uterus but not in blood or spleens expressed higher levels of estrogen receptors. The injection of estrogen into mice increased the proportion of γδT cells in uterus but not in spleens in vivo via CXCR3‐CXCL10 chemokine axis. In addition, we found that estrogen enhanced the production of IL‐17 but not IFN‐γ in vivo and in vitro via interferon regulatory factor 4 but not RORγt and pSTAT3 at mRNA and protein levels. The analysis of cell transcriptome sequence further identified multiple differentially expressed genes between estrogen and control γδT cells. Our study demonstrated that estrogen directly act on γδT cells in uterus to enhance the production of IL‐17 that might promote the invasion of trophocytes. Furthermore, our study might provide a new idea that estrogen increased the prevalence of autoimmune diseases in women by enhancing γδT cell‐derived IL‐17 production in uterus and uncover the critical pathological roles for estrogen in the development of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Aims: Immunomodulatory effects of parasitic infections on the outcomes of allergic or autoimmune disorders have been addressed in many experimental studies. We examined the effects of Plasmodium yoelii 17X NL (Py) infection on collagen‐induced arthritis (CIA). Methods and Results: Male DBA/1J mice were immunized with bovine type II collagen (IIC). Py inoculation was induced at three different time points (1, 4 weeks after or 4 weeks before the immunization). Only the inoculation at 4 weeks after IIC immunization significantly inhibited arthritis development. Non‐malarial anaemia induced by phenylhydrazine hydrochloride (PHZ) did not affect arthritis development. In the infected mice, anti‐IIC IgG levels were transiently reduced. In addition, splenic production of pro‐arthritic cytokines (IL‐17 and TNF‐α) and IFN‐γ decreased, whereas IL‐10 production increased. Flow cytometric analysis clarified that the main IL‐10 producers in Py‐infected mice had the CD4+CD25–Foxp3– phenotype, presumably Tr1 cells. Conclusion: We demonstrated that experimental malarial infection alleviated autoimmune arthritis via immunomodulation, suggesting the importance of malaria in the hygiene hypothesis and the significance of searching for therapeutic immunomodulatory molecules from malarial parasites. [ABSTRACT FROM AUTHOR]

Viral infections are a major threat to the human population due to the lack of selective therapeutic measures. The morbidity and mortality reported worldwide are very alarming against viral pathogens. The proinflammatory environment is required for viral inhibition by initiating the host immune response. The host immune response fights these pathogens by secreting different cytokines. Interleukin‐17 (IL‐17) a proinflammatory cytokine mainly produced by T helper type 17 cells, plays a vital role in the regulation of host immune response against various pathogens, including viruses. However, dysregulated production of IL‐17 induces chronic inflammation, autoimmune disorders, and may lead to cancer. Recent studies suggest that IL‐17 is not only involved in the antiviral immune response but also promotes virus‐mediated illnesses. In this review, we discuss the protective and pathogenic role of IL‐17 against various viral infections. A detailed understanding of IL‐17 during viral infections could contribute to improve therapeutic measures and enable the development of an efficient and safe IL‐17 based immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Inherited chronic mucocutaneous candidiasis (CMC) is often caused by inborn errors of immunity, impairing the response to, or the production of IL‐17A and IL‐17F. About half of the cases carry STAT1 gain‐of‐function (GOF) mutations. Only few patients have been reported with mutations of TRAF3IP2, a gene encoding the adaptor ACT1 essential for IL‐17 receptor(R) signaling. We investigated a 10‐year‐old girl with CMC, carrying a heterozygous variant of STAT1 and compound heterozygous variants of TRAF3IP2. Methods: By flow cytometry, STAT1 levels and phosphorylation (CD14+) as well as IL‐17A, IL‐22, IFN‐γ, and IL‐4 production (memory CD4+ T cells) were determined. ACT1 expression and binding to IL‐17RA were assessed by Western blot and co‐immunoprecipitation in HEK‐293T cells transfected with plasmids encoding wild‐type or mutant HA‐tagged ACT1 and Flag‐IL‐17RA. We evaluated IL‐17A responses by measuring luciferase induction under a NF‐κB‐driven reporter system in HEK‐293T cells and Gro‐α secretion in fibroblasts. Results: A STAT1 variant (c.1363G>A/p.V455I) was identified by next‐generation sequencing and classified as likely non‐pathogenic as functional testing revealed normal STAT1 expression and phosphorylation upon IFN‐γ. We also found compound heterozygous variants (c.1325A>G/p.D451G and c.1335delA/p.K454fs11*) of TRAF3IP2. By overexpression, despite normal protein expression, and impaired (K454fs11*) or normal (D451G) interaction with IL‐17RA, both mutant alleles resulted in impaired NF‐κB activation. Patient's fibroblasts displayed abolished GRO‐α secretion upon IL‐17A stimulation. Finally, ex vivo CD4+ T cells showed increased IL‐17A, IL‐22, and IL‐4 and normal low IFN‐γ expression upon stimulation. Conclusion: We identify novel compound heterozygous variants of TRAFP3IP2 causing autosomal recessive ACT1 deficiency in a child with CMC and provide a review of the current literature. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) have been identified within dental pulp tissues of exfoliated deciduous (SHEDs) and permanent (DPSCs) teeth. Although differences in their proliferative and differentiation properties were revealed, variability in SHEDs and DPSCs responsiveness to growth factors and cytokines have not been studied before. Here, we investigated the influence of interleukin‐17 (IL‐17) and basic fibroblast growth factor (bFGF) on stemness features of SHEDs and DPSCs by analyzing their proliferation, clonogenicity, cell cycle progression, pluripotency markers expression and differentiation after 7‐day treatment. Results indicated that IL‐17 and bFGF differently affected SHEDs and DPSCs proliferation and clonogenicity, since bFGF increased proliferative and clonogenic potential of both cell types, while IL‐17 similarly affected SHEDs, exerting no effects on adult counterparts DPSCs. In addition, both factors stimulated NANOG, OCT4, and SOX2 pluripotency markers expression in SHEDs and DPSCs showing diverse intracellular expression patterns dependent on MSCs type. As for the differentiation capacity, both factors displayed comparable effects on SHEDs and DPSCs, including stimulatory effect of IL‐17 on early osteogenesis in contrast to the strong inhibitory effect showed for bFGF, while having no impact on SHEDs and DPSCs chondrogenesis. Moreover, bFGF combined with IL‐17 reduced CD90 and stimulated CD73 expression on both types of MSCs, whereas each factor induced IL‐6 expression indicating its' role in IL‐17/bFGF‐modulated properties of SHEDs and DPSCs. All these data demonstrated that dental pulp MSCs from primary and permanent teeth exert intrinsic features, providing novel evidence on how IL‐17 and bFGF affect stem cell properties important for regeneration of dental pulp at different ages. [ABSTRACT FROM AUTHOR]

The management of acute pancreatitis (AP) remains a challenge to clinicians worldwide for limited effective interventions. Retinoid orphan receptor gamma t (RORγt) is a therapeutic target for several diseases; however, it is unclear whether inhibiting RORγt can ameliorate AP. The relative expression of RORγt, IL‐17 and IL‐23 in the peripheral blood mononuclear cells of AP patients was measured by RT‐PCR. An AP mouse model was induced by ceruletide, and SR1001 was injected before ceruletide administration. RORγt+ cells, T helper 17 cells (Th17), regulatory T cells (Tregs) and γδ T cells were assessed in the pancreas and spleen by flow cytometry. Higher RORγt expression in patients indicated the potential role of RORγt in AP progression. Analyses of the IL‐17/IL‐23 axis confirmed its role. SR1001 significantly alleviated AP histologically in the mouse model. Serum levels of amylase, IL‐6, TNFalpha, IL‐17 and IL‐23 decreased upon SR1001 treatment. SR1001 selectively decreased the number of RORγt+, Th17, Tregs and γδ T cells in the pancreas but not the spleen. Collectively, these results showed that SR1001 exerted therapeutic effects on AP by suppressing IL‐17‐secreting Th17 and γδ T cells in the pancreas. Thus, SR1001 may be a promising drug for the treatment of AP in the clinic. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) is a common complication of cardiopulmonary bypass (CPB), associated with increased mortality in surgical patients. It is well-proven that Th17 and its hallmark cytokine, IL-17, contribute to AKI development. Since the RAR-related orphan receptor C (RORC) gene is a master regulator of the Th17 differentiation, we aimed to evaluate the association between its polymorphisms, CPB-AKI and plasma IL-17 levels among Iranian patients undergoing CPB.Method: Totally, 138 patients undergoing CPB in Bandar Abbas, Iran, were enrolled. The allele and genotype frequencies of the selected SNPs were determined using PCR-SSP. IL-17 serum level was determined using an enzyme-linked immunosorbent assay.Results: Rs9017 GG genotype and G allele were associated with increased risk of CPB-AKI (OR = 3, 95% CI = 1.4-6.6 and OR = 2.3, 95% CI = 1.3-3.9, respectively) while A allele was protective against the disease (OR = 0.4, 95% CI = 0.3-0.7, p = .02). There was not a statistically significant interaction between the three genotypes of rs9017 and AKI disease with IL-17 serum level before (p = .9) and after (p = .6) the operation. The IL-17 serum level before surgery was significantly higher in patients carrying GG genotype compared to GA genotype (p = .017).Conclusion: Our results showed that the rs9017 GG genotype was associated with an increased level of IL-17 and risk of CBP-AKI in the Iranian population. Our current results suggest that the rs9017 GG genotype could be a probable predictor of AKI after cardiac surgery. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic autoimmune skin disorder that can vary in severity and extent of disease. While localized disease can be managed with topical medications, widespread disease often requires systemic therapy including biologics. This medication class targets different components of the immune system and thus modulates disease activity. The biologic secukinumab is a human monoclonal antibody against interleukin‐17A used for the treatment of psoriasis and psoriatic arthritis; cases of inflammatory bowel disease (IBD) have been observed in clinical trials to be associated with this medication. This review aims to provide evidence for the relationships between secukinumab treatment and the development of IBD. We have examined review articles and original research papers, published between 2010 and 2020, using the following keywords: psoriasis, psoriatic arthritis, secukinumab, IBD, Crohn's disease, ulcerative colitis, interleukin‐17, IL‐17, IL‐17 inhibitor. Case reports have noted an association between secukinumab use and IBD and have called for IBD pre‐screening in patients who will be prescribed this medication. Clinical trials concluded that secukinumab was associated with IBD, while retrospective studies have had mixed results, with most studies showing no statistical significance between secukinumab and IBD but having seen patients with history of IBD or family histories experience new‐onset IBD or flare‐ups. Given the utilization of secukinumab as a therapy for psoriasis and psoriatic arthritis, appropriate screening and risk stratification could help limit morbidity and mortality that can be associated with secukinumab‐induced IBD. [ABSTRACT FROM AUTHOR]

Gamma‐delta (γδ) T cells are the bridge between natural and adaptive immunity. In the present study, peripheral blood was collected from 13 patients with advanced schistosomiasis (schistosomiasis group) and 13 uninfected people (control group) to investigate the γδ T cells and their subtypes in human schistosomiasis. Compared with the control group, the proportion of Vδ1 cells and CD27+Vδ1+ cells in the schistosomiasis group increased significantly, while CD27− cells and CD27−Vδ1− cells decreased. Only the level of IL‐17A differed between the groups, being significantly decreased in the schistosomiasis group. In the schistosomiasis group, there were no correlations between the liver fibrosis and subsets of γδ T cells, or the level of cytokines. Additionally, the level of IL‐17A correlated positively with the proportion of CD27− Vδ1− cells. Thus, there was a higher frequency of circulating Vδ1 γδT cells in patients with advanced schistosomiasis. The decreased IL‐17A might be related to the reduction in CD27−Vδ1− cell. [ABSTRACT FROM AUTHOR]