Associations of different inflammatory factors with atherosclerosis among patients with psoriasis vulgaris.

Background: This study aimed to measure the associations between different inflammatory factors, namely interleukin (IL)-17A, tumor necrosis factor (TNF)-α, and high-sensitivity C-reactive protein (hs-CRP), and atherosclerosis in patients with psoriasis vulgaris. Methods: A cross-sectional study was conducted at two hospitals in Hanoi, Vietnam. A total of 125 patients with psoriasis vulgaris and 50 healthy controls were recruited. Clinical characteristics and atherosclerosis were assessed. IL-17A, TNF-α, and hs-CRP levels were measured. Results: Psoriasis vulgaris patients with atherosclerosis had higher levels of hs-CRP (median = 1.22; interquartile range-IQR = 0.34-12.11) and IL-17A (median = 1.30; IQR = 0.43-4.28), but a lower level of TNF-α (median = 0.54; IQR = 0.13-3.41) compared to those without atherosclerosis (p < 0.05). Only LogIL-17A was positively related to atherosclerosis in psoriasis patients (Odds Ratio-OR = 2.16, 95% CI = 1.06-4.38, p < 0.05). After excluding systemically treated patients, LogIL-17A and Log TNF-α were associated with the likelihood of atherosclerosis (p < 0.05). Conclusion: This study suggests a link between elevated levels of IL-17A and TNF-α and subclinical atherosclerosis. Further investigation on a larger scale is required to establish the causality of this relationship.

Blocking CTLA-4 promotes pressure overload-induced heart failure via activating Th17 cells.

Targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) with specific antibody offers long-term benefits for cancer immunotherapy but can cause severe adverse effects in the heart. This study aimed to investigate the role of anti-CTLA-4 antibody in pressure overload-induced cardiac remodeling and dysfunction. Transverse aortic constriction (TAC) was used to induce cardiac hypertrophy and heart failure in mice. Two weeks after the TAC treatment, mice received anti-CTLA-4 antibody injection twice a week at a dose of 10 mg/kg body weight. The administration of anti-CTLA-4 antibody exacerbated TAC-induced decline in cardiac function, intensifying myocardial hypertrophy and fibrosis. Further investigation revealed that anti-CTLA-4 antibody significantly elevated systemic inflammatory factors levels and facilitated the differentiation of T helper 17 (Th17) cells in the peripheral blood of TAC-treated mice. Importantly, anti-CTLA-4 mediated differentiation of Th17 cells and hypertrophic phenotype in TAC mice were dramatically alleviated by the inhibition of interleukin-17A (IL-17A) by an anti-IL-17A antibody. Furthermore, the C-X-C motif chemokine receptor 4 (CXCR4) antagonist AMD3100, also reversed anti-CTLA-4-mediated cardiotoxicity in TAC mice. Overall, these results suggest that the administration of anti-CTLA-4 antibody exacerbates pressure overload-induced heart failure by activating and promoting the differentiation of Th17 cells. Targeting the CXCR4/Th17/IL-17A axis could be a potential therapeutic strategy for mitigating immune checkpoint inhibitors-induced cardiotoxicity.

Interleukin-17A (IL-17A) is involved in antibody specificity to conformational epitopes.

The specificity of antibodies (Ab) is essential for the precise recognition of foreign or dangerous molecules. We have shown that mice infected with non-pathogenic Lactate Dehydrogenase Elevating Virus (LDV) inoculated with human growth hormone (hGH) or Ovalbumin (OVA), exhibit modified specificity of anti-hGH or anti-OVA Ab associated with the secretion of IFN-γ, IL-13, and IL-17. Cytokines are directly or indirectly involved in the isotypes, specificity, and affinity of Ab. Accordingly, here we investigated the effect of IL-17 neutralization on Ab specificities to OVA and Diphtheria Toxoid (DTx) in a mouse model of viral infection. Thereby, we employed an anti-cytokine "auto-vaccination" with an OVA/IL-17A complex or a Monoclonal Ab (MAb) anti-IL-17A (MM17/F3). Competitive ELISA assays were used to estimate the quality of the humoral immune response and the amount of Abs to conformational versus linear antigenic determinants. Results indicated that the OVA/IL-17A complex increased Abs levels to conformational epitopes of OVA, while LDV prolonged antibodies for a longer period. Mice treated with MM17F3 MAb showed an increase in Abs to conformational epitopes of OVA. A similar effect, confirmed by a competitive Western-blot assay, was produced by LDV. Moreover, an increased level of IgM, IgG1, and IgG2a was found in infected animals. Similarly, MAb anti-IL-17A treatment increased the proportion of Ab to conformational epitopes of DTx in uninfected mice, while LDV decreased this parameter. In conclusion, our findings demonstrate a correlation between IL-17A neutralization and a change in Ab specificity to OVA or DTx, presenting a novel strategy for obtaining Abs with higher specificity.

Exploring the mechanism by which Angelica sinensis improves haematopoietic function in aplastic anaemia.

Angelica sinensis (AS) can improve the haematopoietic function, but the treatment mechanism is unknown. Transfusion dependency was estimated by Kaplan-Meier survival analyses and Cox proportional-hazard model in AS treated apalstic anemia (AA) patients. After that, the AA GEO database was analysed, the up differentially expressed genes (DEGs) of AA were combined with AS targets for the intersection of targets. After the AA mouse model was established, the effect of AS was confirmed by haematopoietic function tests. The same experiment plus mitochondrial apoptotic pathway tests in vivo were performed in Angelica sinensis polysaccharide (ASP)-treated mice, the key ingredient in AS. For in vitro experiment, bone marrow nucleated cells (BMNCs) were tested. Clinical data confirmed that the level of transfusion dependency and IL17A were lower in AS-users compared to non-AS users (p < 0.001). The intersection of targets between AA and AS most concentrated on inflammation and apoptosis. Then, the same effect was found in AS treated AA mice model. In both in vivo and in vitro tests, ASP demonstrated the ability to mitigate P38/MAPK-induced Bax-associated mitochondrial apoptosis, while also reducing the levels of activated Th17 cells and alleviating abnormal cytokine levels. So, the protective effect of AS and ASP on hematopoietic function lies in their ability to prevent apoptosis.

Dendritic Cells Promote the Differentiation of ILCs into NCR-ILC3s in the Lungs of Mice Exposed to Cigarette Smoke.

The involvement of Group 3 innate lymphoid cells (ILC3s) and dendritic cells (DCs) in chronic lung inflammation has been increasingly regarded as the key to understand the inflammatory mechanisms of smoke-related chronic obstructive pulmonary disease (COPD). However, the mechanism underlying the engagement of both remains unclear. Our study aimed to explore NCR-ILC3 differentiation in the lungs of mice exposed to cigarette smoke (CS) and to further investigate whether DCs activated by CS exposure contribute to the differentiation of ILCs into NCR-ILC3s. The study involved both in vivo and in vitro experiments. In the former, the frequencies of lung NCR-ILC3s and NKp46-IL-17A+ ILCs and the expression of DCs, CD40, CD86, IL-23, and IL-1ß quantified by flow cytometry were compared between CS-exposed mice and air-exposed mice. In the latter, NKp46-IL-17A+ ILC frequencies quantified by flow cytometry were compared after two cocultures, one involving lung CD45+Lin-CD127+ ILCs sorted from air-exposed mice and DCs sifted by CD11c magnetic beads from CS-exposed mice and another including identical CD45+Lin-CD127+ ILCs and DCs from air-exposed mice. The results indicated significant increases in the frequencies of NCR-ILC3s and NKp46-IL-17A+ ILCs; in the expression of DCs, CD40, CD86, IL-23, and IL-1ß in CS-exposed mice; and in the frequency of NKp46-IL-17A+ ILCs after the coculture with DCs from CS-exposed mice. In conclusion, CS exposure increases the frequency of lung ILCs and NCR-ILC3s. CS-induced DC activation enhances the differentiation of ILCs into NCR-ILC3s, which likely acts as a mediating step in the involvement of NCR-ILC3s in chronic lung inflammation.

Fluoride induces hepatointestinal damage and vitamin B2 mitigation by regulating IL-17A and Bifidobacterium in ileum.

INTRODUCTION: Fluorosis is a global public health disease affecting more than 50 countries and 500 million people. Excessive fluoride damages the liver and intestines, yet the mechanisms and therapeutic approaches remain unclear. OBJECTIVES: To explore the mechanisms by which fluoride-induced intestinal-hepatic damage and vitamin B2 alleviation. METHODS: Fluoride and/or vitamin B2-treated IL-17A knockout and wild-type mouse models were established, the morphological and functional changes of liver and gut, total bile acid biosynthesis, metabolism, transport, and regulation of FXR-FGF15 signaling pathways were evaluated, the ileal microbiome was further analyzed by 16S rDNA sequence. Finally, Bifidobacterium supplementation mouse model was designed and re-examined the above indicators. RESULTS: The results demonstrated that fluoride induced hepatointestinal injury and enterohepatic circulation disorder by altering the synthesis, transporters, and FXR-FGF15 pathway regulation of total bile acid. Importantly, the ileum was found to be the most sensitive and fluoride changed ileal microbiome particularly by reducing abundance of Bifidobacterium. While vitamin B2 supplementation attenuated fluoride-induced enterohepatic circulation dysfunction through IL-17A and ileal microbiome, Bifidobacterium supplementation also reversed fluoride-induced hepatointestinal injury. CONCLUSION: Fluoride induces morphological and functional impairment of liver and gut tissues, as well as enterohepatic circulation disorder by altering total bile acid (TBA) synthesis, transporters, and FXR-FGF15 signaling regulation. Vitamin B2 attenuated fluoride-induced enterohepatic circulation disorder through IL-17A knockout and ileal microbiome regulation. The ileum was found to be the most sensitive to fluoride, leading to changes in ileal microbiome, particularly the reduction of Bifidobacterium. Furthermore, Bifidobacterium supplementation reversed fluoride-induced hepatointestinal injury. This study not only elucidates a novel mechanism by which fluoride causes hepatointestinal toxicity, but also provides a new physiological function of vitamin B2, which will be useful in the therapy of fluorosis and other hepatoenterological diseases.

Association of IL-17A and IL-10 Polymorphisms with Juvenile Idiopathic Arthritis in Finnish Children.

To analyze the role of interleukin IL-17A and IL-10 polymorphisms in susceptibility to juvenile idiopathic arthritis (JIA), 98 Finnish children and adolescents with JIA were studied. Data from the 1000 Genomes Project, consisting of 99 healthy Finns, served as the controls. The patients were analyzed for four IL-17A and three IL-10 gene-promoter polymorphisms, and the serum IL-17A, IL-17F, IL-10, and IL-6 levels were determined. The IL-17A rs8193036 variant genotypes (CT/CC) were more common among the patients than controls, especially in those with polyarthritis (OR 1.93, 95% CI 1.11-3.36; p = 0.020). IL-17A rs2275913 minor allele A was more common in patients (OR 1.45, 95% Cl 1.08-1.94; p = 0.014) and especially among patients with oligoarthritis and polyarthritis than the controls (OR 1.61, 95%CI 1.06-2.43; p = 0.024). Carriers of the IL-17A rs4711998 variant genotype (AG/AA) had higher serum IL-17A levels than those with genotype GG. However, carriers of the variant genotypes of IL-17A rs9395767 and rs4711998 appeared to have higher IL-17F levels than those carrying wildtype. IL-10 rs1800896 variant genotypes (TC/CC) were more abundant in patients than in the controls (OR 1.97, 95%CI 1.06-3.70; p = 0.042). Carriers of the IL-10 rs1800896 variant genotypes had lower serum levels of IL-17F than those with wildtype. These data provide preliminary evidence of the roles of IL-17 and IL-10 in the pathogenesis of JIA and its subtypes in the Finnish population. However, the results should be interpreted with caution, as the number of subjects included in this study was limited.

IL-17A Drives Oxidative Stress and Cell Growth in A549 Lung Epithelial Cells: Potential Protective Action of Oleuropein.

IL-17A drives inflammation and oxidative stress, affecting the progression of chronic lung diseases (asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis). Oleuropein (OLP) is a polyphenolic compound present in olive oil and widely included in the Mediterranean diet. It exerts antioxidant and anti-inflammatory activities, oxidative stress resistance, and anticarcinogenic effects with a conceivable positive impact on human health. We hypothesized that OLP positively affects the mechanisms of oxidative stress, apoptosis, DNA damage, cell viability during proliferation, and cell growth in alveolar epithelial cells and tested its effect in a human alveolar epithelial cell line (A549) in the presence of IL-17A. Our results show that OLP decreases the levels of oxidative stress (Reactive Oxygen Species, Mitochondrial membrane potential) and DNA damage (H2AX phosphorylation-ser139, Olive Tail Moment data) and increases cell apoptosis in A549 cells exposed to IL-17A. Furthermore, OLP decreases the number of viable cells during proliferation, the migratory potential (Scratch test), and the single cell capacity to grow within colonies as a cancer phenotype in A549 cells exposed to IL-17A. In conclusion, we suggest that OLP might be useful to protect lung epithelial cells from oxidative stress, DNA damage, cell growth, and cell apoptosis. This effect might be exerted in lung diseases by the downregulation of IL-17A activities. Our results suggest a positive effect of the components of olive oil on human lung health.

Fluoride induces immunotoxicity by regulating riboflavin transport and metabolism partly through IL-17A in the spleen.

The impairment of the immune system by fluoride is a public health concern worldwide, yet the underlying mechanism is unclear. Both riboflavin and IL-17A are closely related to immune function and regulate the testicular toxicity of fluoride. However, whether riboflavin or IL-17A is involved in fluoride-induced immunotoxicity is unknown. Here, we first established a male ICR mouse model by treating mice with sodium fluoride (NaF) (100 mg/L) via the drinking water for 91 days. The results showed that fluoride increased the expression of the proinflammatory factors IL-1ß and IL-17A, which led to splenic inflammation and morphological injury. Moreover, the expression levels of the riboflavin transporters SLC52A2 and SLC52A3; the transformation-related enzymes RFK and FLAD1; and the key mitochondrial functional determinants SDH, COX, and ATP in the spleen were measured via real-time PCR, Western blotting, and ELISA. The results revealed that fluoride disrupted riboflavin transport, transformation, metabolism, and mitochondrial function. Furthermore, wild-type (WT) and IL-17A knockout (IL-17A-/-) C57BL/6 J male mice of the same age were treated with NaF (24 mg/kg·bw, equivalent to 100 mg/L) and/or riboflavin sodium phosphate (5 mg/kg·bw) via gavage for 91 days. Similar parameters were evaluated as above. The results confirmed that fluoride increased riboflavin metabolism through RFK but not through FLAD1. Fluoride also affected mitochondrial function and activated neutrophils (marked with Ly6g) and macrophages (marked with CD68) in the spleen. Interestingly, IL-17A partly mediated fluoride-induced riboflavin metabolism disorder and immunotoxicity in the spleen. This work not only reveals a novel toxic mechanism for fluoride but also provides new clues for exploring the physiological function of riboflavin and for diagnosing and treating the toxic effects of fluoride in the environment.

IL-17A Cytokine-Regulated Glut1 Expression in Placenta Cells.

Trophoblasts, the principal cellular component of the placenta, play an important role in nutrient and gas exchange. Previous studies have indicated that maternal immune activation (MIA) leads to an elevation in IL-17A cytokine levels in maternal serum, subsequently influencing fetal brain development during pregnancy. In this study, we aimed to elucidate the impact of the IL-17A cytokine on placental function. First, we treated JAR and JEG-3, which is a placenta cell line, with IL-17A in a concentration-dependent or time-dependent manner and observed cell morphology and viability. It was confirmed that treatment with IL-17A or a double-stranded RNA mimic (PolyI:C) had no effect on the morphology or cell viability. IL-17A treatment increased the expression of IL-17R at the mRNA and protein levels, and Poly(I:C) increased the levels of IFNγ and TNFα. Additionally, PPARγ, known as a metabolism regulator, was increased by IL-17A treatment. Also, we observed that the expression of Glut1 and Glut3 was increased by IL-17A treatment. To confirm this, we examined the expression of transporters in the placental tissue of the MIA rodent model, and we observed that mRNA expression of glut1 and glut3 was significantly increased. However, the expression of Gltu1 and Glut3 was observed to be significantly inhibited in the brains of MIA-induced offspring. This study suggests that IL-17A increases signaling through IL-17R in the placenta and fetal brain tissue; however, there is a mechanism for regulating the expression of glucose transporters by increased IL-17A in the placenta.

αPD-1 immunotherapy promotes IL-17A production and promotes the formation of acute radiation-induced lung injury.

BACKGROUND: Radiotherapy (RT) is essential in the treatment of thoracic neoplasms. Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have significantly improved the clinical management of non-small cell lung carcinoma (NSCLC). OBJECTIVE: This study aimed to investigate the impact of combining anti-PD-1 (αPD-1) immunotherapy with radiotherapy on lung injury. Additionally, it investigates the role and mechanism of interleukin (IL)-17A, a pro-inflammatory cytokine involved in immune regulation, in lung injury arising from this combination treatment. METHODS: Experiments were conducted using a PD-1 deficient mouse model to simulate acute radiation-induced lung injury. Inbred female BALB/c wild-type (WT) mice and PD-1-/- mice were divided into six groups: WT group, PD-1-/- group, WT_LIR + IgG group, PD-1-/-_LIR + IgG group, WT_LIR + αIL-17A group, and PD-1-/-_LIR + αIL-17A group. The mice were subjected to 8 Gy × 3 irradiation in both lungs. Various methods including histological scoring, immunofluorescence, qPCR, and flow cytometry were employed to analyze the role of IL-17A in lung injury and the effect of PD-1 gene deletion on the severity of radiation-induced lung injury. RESULTS: The PD-1-/-_LIR mice exhibited evident radiation-induced lung injury after receiving 8 Gy × 3 doses in both lungs. The expression level of IL-17A peaked at 2 weeks. Lung injury-related factors IFN-γ, TNF-α, IL-6, and RORγt in the PD-1-/-_LIR groups increased 2 weeks after irradiation. The CD4+ and CD8+ T cells in lung tissue of the PD-1-/-_LIR mice significantly increased. Post αIL-17A administration, the incidence of alveolitis in the treatment group decreased, the expression levels of lung injury-related factors IFN-γ, TNF-α, IL-6, RORγt, TGF-ß1, and IL-17A decreased, and the CD4+ and CD8+ T cells in lung tissue significantly declined. Throughout the observation period, the survival rate of the mice in the treatment group was significantly higher than that of the isotype control group (60% vs 0%, P = 0.011). CONCLUSION: Combining αPD-1 immunotherapy with radiotherapy in mice can induce radiation-induced lung injury, with IL-17A playing a critical role in this process. αIL-17A administration significantly mitigated radiation-induced lung injury caused by the combination of αPD-1 immunotherapy and radiotherapy, improving mouse survival. This finding offers a promising treatment target for lung injury resulting from the combination of αPD-1 immunotherapy and radiotherapy.

Transcutaneous auricular vagus nerve stimulation improves social deficits through the inhibition of IL-17a signaling in a mouse model of autism.

Background: Maternal exposure to inflammation is one of the causes of autism spectrum disorder (ASD). Electrical stimulation of the vagus nerve exerts a neuroprotective effect via its anti-inflammatory action. We thus investigated whether transcutaneous auricular vagus nerve stimulation (taVNS) can enhance social abilities in a mouse model of ASD induced by maternal immune activation (MIA). Methods: ASD mouse model were constructed by intraperitoneal injection of polyinosinic:polycytidylic acid (poly (I:C)). TaVNS with different parameters were tested in ASD mouse model and in C57BL/6 mice, then various behavioral tests and biochemical analyses related to autism were conducted. ASD model mice were injected with an interleukin (IL)-17a antibody into the brain, followed by behavioral testing and biochemical analyses. Results: TaVNS reduced anxiety, improved social function, decreased the number of microglia, and inhibited M1 polarization of microglia. Additionally, taVNS attenuated the expression of the IL-17a protein in the prefrontal cortex and blood of ASD model mice. To examine the possible involvement of IL-17a in taVNS-induced neuroprotection, we injected an IL-17a antibody into the prefrontal cortex of ASD model mice and found that neutralizing IL-17a decreased the number of microglia and inhibited M1 polarization. Furthermore, neutralizing IL-17a improved social function in autism model mice. Conclusion: Our study revealed that reduced neuroinflammation is an important mechanism of taVNS-mediated social improvement and neuroprotection against autism. This effect of taVNS could be attributed to the inhibition of the IL-17a pathway.

Narciclasine induces colon carcinoma cell apoptosis by inhibiting the IL-17A/Act1/TRAF6/NF-κB signaling pathway.

IL-17 A is a promoter of colorectal cancer initiation and progression. Narciclasine is a polyhydroxy alkaloid compound isolated from Narcissus plants, which has potent anti-inflammatory and antitumor actions. The effects of narciclasine on colorectal tumors were evaluated, with a focus on IL-17 A. Narciclasine reduced the growth of HCT-116 and SW-480 colon cancer cells in vitro and in vivo in murine xenografts. The results of flow cytometry on JC-1 and Annexin V/PI revealed that narciclasine significantly reduced the mitochondrial membrane potential and induced apoptosis, findings confirmed by western blotting results of reduced Bcl-2 and enhanced Bax expression, as well as accumulation of cleaved Caspase-3, Caspase-8, Caspase-9, and cytoplasmic Cytochrome-c. After narciclasine incubation, IL-17 A, Act1, and TRAF6 were down-regulated, while p-P65 (Ser536) accumulated in the cytoplasm, a finding confirmed by laser scanning confocal microscopy. IL17A substitution could partly reverse these narciclasine effects while they were elevated by IL17A silencing. Moreover, IL-17 A, Act1, and TRAF6 were significantly expressed to greater extents in human colorectal cancer compared to normal adjacent tissue specimens and were closely linked with a poor prognosis. This study provided evidence that narciclasine may be a useful therapeutic drug for colorectal cancer treatment through its actions in down-regulating the L-17A/Act1/TRAF6/NF-κB anti-apoptotic signaling pathway.

T-Cell Epitope Mapping of SARS-CoV-2 Reveals Coordinated IFN-γ Production and Clonal Expansion of T Cells Facilitates Recovery from COVID-19.

BACKGROUND: T-cell responses can be protective or detrimental during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, the underlying mechanism is poorly understood. METHODS: In this study, we screened 144 15-mer peptides spanning the SARS-CoV-2 spike, nucleocapsid (NP), M, ORF8, ORF10, and ORF3a proteins and 39 reported SARS-CoV-1 peptides in peripheral blood mononuclear cells (PBMCs) from nine laboratory-confirmed coronavirus disease 2019 (COVID-19) patients (five moderate and four severe cases) and nine healthy donors (HDs) collected before the COVID-19 pandemic. T-cell responses were monitored by IFN-γ and IL-17A production using ELISA, and the positive samples were sequenced for the T cell receptor (TCR) ß chain. The positive T-cell responses to individual SARS-CoV-2 peptides were validated by flow cytometry. RESULTS: COVID-19 patients with moderate disease produced more IFN-γ than HDs and patients with severe disease (moderate vs. HDs, p < 0.0001; moderate vs. severe, p < 0.0001) but less IL-17A than those with severe disease (p < 0.0001). A positive correlation was observed between IFN-γ production and T-cell clonal expansion in patients with moderate COVID-19 (r = 0.3370, p = 0.0214) but not in those with severe COVID-19 (r = -0.1700, p = 0.2480). Using flow cytometry, we identified that a conserved peptide of the M protein (Peptide-120, P120) was a dominant epitope recognized by CD8+ T cells in patients with moderate disease. CONCLUSION: Coordinated IFN-γ production and clonal expansion of SARS-CoV-2-specific T cells are associated with disease resolution in COVID-19. Our findings contribute to a better understanding of T-cell-mediated immunity in COVID-19 and may inform future strategies for managing and preventing severe outcomes of SARS-CoV-2 infection.

Janus kinase inhibitor tofacitinib successfully treated palmoplantar pustulosis after switching from secukinumab: A case report and review of the literature.

Palmoplantar pustulosis (PPP) is a chronic inflammatory recurrent disease characterized by sterile pustules involving palms and/or feet. Presently, there are no standard recommended treatment regimens. Tofacitinib is an oral Janus kinase (JAK) inhibitor, mainly acts on JAK 1 and 3 and has been approved for the treatment of rheumatoid arthritis in adults. Herein, we present a case of a patient with PPP who did not respond to IL-17A inhibitor secukinumab but was successfully treated by the JAK inhibitor tofacitinib.

An in vitro study of the impact of IL-17A and IL-22 on ciliogenesis in nasal polyps epithelium via the Hippo-YAP pathway.

BACKGROUND: Cilia loss and impaired motile ciliary functions are among the typical pathological features of chronic rhinosinusitis with nasal polyps (CRSwNP). IL17A and IL22 are the canonical cytokines of type 3 inflammation, exhibiting similar functional effects on epithelial cells. In this study, we sought to examine the effects of IL17A and IL22 on ciliated cells and investigate the potential involvement of Hippo-YAP signaling in their influence on ciliogenesis. METHODS: We assessed both the mRNA and protein expression levels of IL17A and IL22 in nasal tissues obtained from patients with CRSwNP and compared them to those from healthy controls. To further explore the impact of IL17A and IL22, we established a primary human nasal epithelial cell model using different concentrations (2 ng/mL, 10 ng/mL, 50 ng/mL) for a duration of 28 days in an air-liquid interface culture. Additionally, we employed the inhibitor verteporfin to investigate whether IL17A and IL22 exert their effects on ciliated cells via the Hippo-YAP pathway. RESULTS: The mRNA and protein levels of IL17A and IL22 in CRSwNP were significantly higher than those in healthy controls, revealing a robust correlation between IL17A and IL22. YAP was highly expressed in the nucleus of ciliated cells in CRSwNP and displayed a positive correlation with clinical symptoms. Both IL17A and IL22 were found to reduce the number of ciliated cells. IL17A, but not IL22, suppressed ciliogenesis by disrupting the proper development and docking of the basal body of ciliated cells, resulting in motile ciliary dysfunctions. Furthermore, the expression of YAP within the nucleus of ciliated cells gradually declined as these cells reached the final stage of differentiation. However, this process was obstructed by IL17A only. YAP inhibitors, such as verteporfin, markedly reversed the effects of IL17A by increasing the proportion of ciliated cells, suppressing nuclear YAP expression in these cells, and enhancing ciliary beating frequency. CONCLUSIONS: Both IL17A and IL22 are overexpressed in nasal epithelium of CRSwNP, which is associated with the impairment of epithelial cell differentiation. Furthermore, IL17A has been shown to exert a disruptive effect on morphogenesis of motile cilia via activation of YAP.

NR2E3 inhibits the inflammation and apoptosis in diabetic retinopathy by regulating the AHR/IL-17A signaling pathway.

Diabetic retinopathy (DR) is the most prevalent microvascular complication of diabetes mellitus, and it is the primary cause of blindness in the working-age population worldwide. Nevertheless, the pathogenic molecular mechanisms of DR remain elusive. Hub genes were identified through bioinformatics analysis in the GSE102485 and GSE60436 datasets. The DR mouse model was induced using streptozotocin (STZ, 150 mg/kg), and pathological changes in retinal tissue were assessed via HE staining. Apoptosis in retinal tissue cells was evaluated by the TUNEL assay. RT-qPCR and ELISA assays were employed to measure hub genes and inflammatory factor levels, respectively. The aryl hydrocarbon receptor (AHR)/interleukin (IL)-17A (AHR/IL-17A) pathway-associated proteins were detected by western blot. In the high glucose (HG)-induced ARPE-19 cells, CCK-8 and flow cytometry were used to perform cell function studies. Six hub genes associated with DR were screened. The expression levels of RHO, PRPH2, CRX, RCVRN, and NR2E3 were reduced, while the COL1A2 was elevated. NR2E3 overexpression reduced inflammatory factor (TNF-α, IL-1ß, and IL-6) and cell apoptosis levels in DR. Furthermore, NR2E3 overexpression promoted HG-induced ARPE-19 cell proliferation. Mechanistically, NR2E3 overexpression facilitated the protein expression of AHR, while suppressing the IL-17 and ACT1 expressions. The introduction of Kyn-101, an AHR inhibitor, notably reversed the inhibitory effects of NR2E3 overexpression on inflammation and apoptosis, which were validated both in vivo and in vitro. NR2E3 inhibits the inflammation and apoptosis by regulating the AHR/IL-17A pathway, providing new insights into the DR treatment.

Iguratimod ameliorates antibody-mediated rejection after renal transplant by modulating the Th17/Treg paradigm.

BACKGROUND: Iguratimod (IGU) is widely used in clinical practice due to its stable anti-inflammatory effects. Our previous studies have confirmed that the proportion of Th17/Treg balance in patients taking IGU altered significantly. This study aims to explore the role of IGU in antibody-mediated rejection (ABMR) and its potential mechanisms. METHODS: We conducted bioinformatics analysis of sequencing data from the GEO database to analyze the abundance of immune cell infiltration in transplanted kidney tissues. In vivo, IGU was intervened in a mice secondary skin transplantation model and a mice kidney transplantation ABMR model, and histological morphology of the grafts were examined by pathological staining, while relevant indicators were determined through qRT-PCR, immunohistochemistry, and enzyme-linked immunosorbent assay, observed T cell differentiation by flow cytometry, and preliminarily assessed the immunosuppressive effect of IGU. In vitro, we established Th17 and Treg cell induction and stimulation differentiation culture systems and added IGU for intervention to explore its effects on their differentiation. RESULTS: Through bioinformatics analysis, we found that Th17 and Treg may play important roles in the occurrence and development of ABMR. In vivo, we found that IGU could effectively reduce the damage caused by ABMR to the grafts, alleviate the infiltration of inflammatory cells in the graft tissues, and reduce the deposition of C4d in the grafts. Moreover, it is also found that IGU regulated the differentiation of Th17 and Treg cells in the spleen and peripheral blood and reduced the expression of IL-17A in the grafts and serum. In addition, same changes were observed in the induction and differentiation culture system of Th17 and Treg cells in vitro after the addition of IGU. CONCLUSION: IGU can inhibit the progression of ABMR by regulating the differentiation of Th17 and Treg cells, providing novel insights for optimizing clinical immunosuppressive treatment regimens.

Pharmacokinetics, Safety, and Immunogenicity of Intravenous and Subcutaneous Single-Dose QX002N Injection in Healthy Subjects: A Randomized, Open, Parallel, Single-Center, Phase I Study.

INTRODUCTION: Interleukin-17A (IL-17A) plays a crucial role in the pathogenesis of ankylosing spondylitis (AS), although not all patients respond to traditional IL-17A antibody treatments. QX002N injection, as a new monoclonal antibody targeting IL-17A, has shown potential in treating AS, offering a new treatment option for patients who do not respond well to existing therapies. METHODS: A randomized, open, parallel, single-center, phase I study was conducted to assess the pharmacokinetics, safety, and immunogenicity of single doses of QX002N injection administered intravenously (IV) or subcutaneously (SC) to healthy Chinese volunteers. Blood samples were collected at specified time intervals, and then serum concentrations of QX002N were analyzed by enzyme-linked immunosorbent assay. RESULTS: Pharmacokinetic analysis of the drug concentration-time data showed that the mean maximum observed serum QX002N concentration (Cmax) was 110 and 33.9 µg/ml, respectively. The average area under the drug concentration-time curves from 0 to the time of the last quantifiable concentration (AUClast) were 52,656 and 36,269 µg·h/ml, respectively and the average area under the drug concentration-time curves from 0 to infinity (AUCinf) were 54,867 and 38,194 µg·h/ml, respectively. The absolute bioavailability of QX002N after SC injection was 69.6%. CONCLUSIONS: Immunogenicity was assessed and all the subjects in this study were Anti-drug antibody (ADA)-negative, which means no subjects appeared to develop immunogenicity to QX002N. All the results testify to the safety of QX002N injection, which is satisfactory after IV or SC dosing in healthy subjects. TRIAL REGISTRATION: www.chinadrugtirals.org.cn , CTR20220430.

Modulation of Alzheimer's disease brain pathology in mice by gut bacterial depletion: the role of IL-17a.

Gut bacteria regulate brain pathology of Alzheimer's disease (AD) patients and animal models; however, the underlying mechanism remains unclear. In this study, 3-month-old APP-transgenic female mice with and without knock-out of Il-17a gene were treated with antibiotics-supplemented or normal drinking water for 2 months. The antibiotic treatment eradicated almost all intestinal bacteria, which led to a reduction in Il-17a-expressing CD4-positive T lymphocytes in the spleen and gut, and to a decrease in bacterial DNA in brain tissue. Depletion of gut bacteria inhibited inflammatory activation in both brain tissue and microglia, lowered cerebral Aß levels, and promoted transcription of Arc gene in the brain of APP-transgenic mice, all of which effects were abolished by deficiency of Il-17a. As possible mechanisms regulating Aß pathology, depletion of gut bacteria inhibited ß-secretase activity and increased the expression of Abcb1 and Lrp1 in the brain or at the blood-brain barrier, which were also reversed by the absence of Il-17a. Interestingly, a crossbreeding experiment between APP-transgenic mice and Il-17a knockout mice further showed that deficiency of Il-17a had already increased Abcb1 and Lrp1 expression at the blood-brain barrier. Thus, depletion of gut bacteria attenuates inflammatory activation and amyloid pathology in APP-transgenic mice via Il-17a-involved signaling pathways. Our study contributes to a better understanding of the gut-brain axis in AD pathophysiology and highlights the therapeutic potential of Il-17a inhibition or specific depletion of gut bacteria that stimulate the development of Il-17a-expressing T cells.