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Fine particulate matter (PM2.5) is the primary air pollutant that is able to induce airway injury. Compelling evidence has shown the involvement of IL‐17A in lung injury, while its contribution to PM2.5‐induced lung injury remains largely unknown. Here, we probed into the possible role of IL‐17A in mouse models of PM2.5‐induced lung injury. Mice were instilled with PM2.5 to construct a lung injury model. Flow cytometry was carried out to isolate γδT and Th17 cells. ELISA was adopted to detect the expression of inflammatory factors in the supernatant of lavage fluid. Primary bronchial epithelial cells (mBECs) were extracted, and the expression of TGF signalling pathway‐, autophagy‐ and PI3K/Akt/mTOR signalling pathway‐related proteins in mBECs was detected by immunofluorescence assay and Western blot analysis. The mitochondrial function was also evaluated. PM2.5 aggravated the inflammatory response through enhancing the secretion of IL‐17A by γδT/Th17 cells. Meanwhile, PM2.5 activated the TGF signalling pathway and induced EMT progression in bronchial epithelial cells, thereby contributing to pulmonary fibrosis. Besides, PM2.5 suppressed autophagy of bronchial epithelial cells by up‐regulating IL‐17A, which in turn activated the PI3K/Akt/mTOR signalling pathway. Furthermore, IL‐17A impaired the energy metabolism of airway epithelial cells in the PM2.5‐induced models. This study suggested that PM2.5 could inhibit autophagy of bronchial epithelial cells and promote pulmonary inflammation and fibrosis by inducing the secretion of IL‐17A in γδT and Th17 cells and regulating the PI3K/Akt/mTOR signalling pathway.

The dysfunction of type II alveolar epithelial cells (AECIIs), mainly manifested by apoptosis, has emerged as a major component of idiopathic pulmonary fibrosis (IPF) pathophysiology. A pivotal mechanism leading to AECIIs apoptosis is mitochondrial dysfunction. Recently, interleukin (IL)‐17A has been demonstrated to have a pro‐fibrotic role in IPF, though the mechanism is unclear. In this study, we report enhanced expression of IL‐17 receptor A (IL‐17RA) in AECIIs in lung samples of IPF patients, which may be related to the accumulation of mitochondria in AECIIs of IPF. Next, we investigated this relationship in bleomycin (BLM)‐induced PF murine model. We found that IL‐17A knockout (IL‐17A−/−) mice exhibited decreased apoptosis levels of AECIIs. This was possibly a result of the recovery of mitochondrial morphology from the improved mitochondrial dynamics of AECIIs, which eventually contributed to alleviating lung fibrosis. Analysis of in vitro data indicates that IL‐17A impairs mitochondrial function and mitochondrial dynamics of mouse primary AECIIs, further promoting apoptosis. PTEN‐induced putative kinase 1 (PINK1)/Parkin signal‐mediated mitophagy is an important aspect of mitochondria homeostasis maintenance. Our data demonstrate that IL‐17A inhibits mitophagy and promotes apoptosis of AECIIs by decreasing the expression levels of PINK1. We conclude that IL‐17A exerts its pro‐fibrotic effects by inducing mitochondrial dysfunction in AECIIs by disturbing mitochondrial dynamics and inhibiting PINK1‐mediated mitophagy, thereby leading to apoptosis of AECIIs.

As a common chronic inflammatory skin disease, psoriasis seriously affects the physical health and psychological well-being of patients. Various clinical treatments for psoriasis have their own drawbacks, so it is important to find effective and safe drugs. Rehmannioside A (ReA) has anti-inflammatory properties and is the main active ingredient in Fuzhengzhiyanghefuzhiyang decoction (FZHFZY), an herbal compound for the treatment of psoriasis. But no studies have been conducted to determine whether ReA alone can treat psoriasis. Therefore, this study was designed to investigate the effect of ReA in the treatment of psoriasis and its potential mechanism of action.ObjectiveAs a common chronic inflammatory skin disease, psoriasis seriously affects the physical health and psychological well-being of patients. Various clinical treatments for psoriasis have their own drawbacks, so it is important to find effective and safe drugs. Rehmannioside A (ReA) has anti-inflammatory properties and is the main active ingredient in Fuzhengzhiyanghefuzhiyang decoction (FZHFZY), an herbal compound for the treatment of psoriasis. But no studies have been conducted to determine whether ReA alone can treat psoriasis. Therefore, this study was designed to investigate the effect of ReA in the treatment of psoriasis and its potential mechanism of action.HaCaT cells were treated with ReA and IL-17A alone for 24 h and 48 h, and the most effective concentrations of ReA and interleukin (IL)-17A were found at 25 μg/mL and 100 ng/mL, respectively. A psoriasis cell model was constructed by stimulating HaCaT cells with IL-17A, followed by intervention with ReA. Cell viability and cell cycle distribution were measured by MTT assay and flow cytometry. The expression levels of keratin family members and chemokines were detected by real-time quantitative PCR (RT-qPCR), the levels of pro-inflammatory cytokines by enzyme-linked immunosorbent assay (ELISA), and key proteins of TRAF6/MAPK signaling pathway by Western blot.MethodsHaCaT cells were treated with ReA and IL-17A alone for 24 h and 48 h, and the most effective concentrations of ReA and interleukin (IL)-17A were found at 25 μg/mL and 100 ng/mL, respectively. A psoriasis cell model was constructed by stimulating HaCaT cells with IL-17A, followed by intervention with ReA. Cell viability and cell cycle distribution were measured by MTT assay and flow cytometry. The expression levels of keratin family members and chemokines were detected by real-time quantitative PCR (RT-qPCR), the levels of pro-inflammatory cytokines by enzyme-linked immunosorbent assay (ELISA), and key proteins of TRAF6/MAPK signaling pathway by Western blot.ReA weaken cell viability, down-regulate the expression of keratin family members (KRT6 and KRT17), restore cell cycle distribution to normal distribution, inhibit the release of pro-inflammatory cytokines (IL-6, IL-8 and IL-1β) and lower the expression of chemokines (S100A7, S100A9 and CXCL2) by interfering with the interaction between HaCaT cells and IL-17A. Thus, it exerts an anti-psoriatic effect by reducing the inflammatory response and inhibiting abnormal proliferation of HaCaT cells. Mechanistically, ReA inhibited the TRAF6/MAPK signaling pathway activated by IL-17A stimulation in HaCaT cells.ResultsReA weaken cell viability, down-regulate the expression of keratin family members (KRT6 and KRT17), restore cell cycle distribution to normal distribution, inhibit the release of pro-inflammatory cytokines (IL-6, IL-8 and IL-1β) and lower the expression of chemokines (S100A7, S100A9 and CXCL2) by interfering with the interaction between HaCaT cells and IL-17A. Thus, it exerts an anti-psoriatic effect by reducing the inflammatory response and inhibiting abnormal proliferation of HaCaT cells. Mechanistically, ReA inhibited the TRAF6/MAPK signaling pathway activated by IL-17A stimulation in HaCaT cells.ReA has in vitro anti-psoriatic effects and may be a new therapeutic agent for psoriasis.ConclusionReA has in vitro anti-psoriatic effects and may be a new therapeutic agent for psoriasis.

ABSTRACT Circadian disruptions and neuroinflammation impact nearly all people with Alzheimer's disease (AD), but their relationships with each other and the impact of their interaction on AD remain to be addressed. Here, we found that amyloid (A)‐β treatment downregulated brain and muscle aryl hydrocarbon receptor nuclear translocator‐like (BMAL) 1 through the hypermethylation of its promoter region in HT22 cells and that the inhibition of DNA methylation ameliorated circadian rhythm disorders and restored BMAL1 protein expression by reversing its hypermethylation in APPswe/PSEN1dE9 (APP/PS1) mice. Critically, increased levels of interleukin (IL)‐17A contributed to BMAL1 downregulation through the hypermethylation of its promoter region, thus leading to circadian disruptions in APP/PS1 mice. Moreover, we revealed that the mitogen‐activated protein kinase (MAPK) pathway was responsible for IL‐17A‐induced DNA methyltransferase (DNMT) 1 upregulation. Taken together, we elucidate a new mechanism connecting IL‐17A with altered DNA methylation of Bmal1, which results in circadian disturbances in an AD mouse model.

The tumor necrosis factor (TNF) and IL-23/IL-17 axes are the main therapeutic targets in spondyloarthritis. Despite the clinical efficacy of blocking either pathway, monotherapy does not induce remission in all patients and its effect on new bone formation remains unclear. We aimed to study the effect of TNF and IL-17A dual inhibition on clinical disease and structural damage using the HLA-B27/human β2-microglobulin transgenic rat model of SpA. Immunized rats were randomized according to arthritis severity, 1 week after arthritis incidence reached 50%, to be treated twice weekly for a period of 5 weeks with either a dual blockade therapy of an anti-TNF antibody and an anti-IL-17A antibody, a single therapy of either antibody, or PBS as vehicle control. Treatment-blinded observers assessed inflammation and structural damage clinically, histologically and by micro-CT imaging. Both single therapies as well as TNF and IL-17A dual blockade therapy reduced clinical spondylitis and peripheral arthritis effectively and similarly. Clinical improvement was confirmed for all treatments by a reduction of histological inflammation and pannus formation (p < 0.05) at the caudal spine. All treatments showed an improvement of structural changes at the axial and peripheral joints on micro-CT imaging, with a significant decrease for roughness (p < 0.05), which reflects both erosion and new bone formation, at the level of the caudal spine. The effect of dual blockade therapy on new bone formation was more prominent at the axial than the peripheral level. Collectively, our study showed that dual blockade therapy significantly reduces inflammation and structural changes, including new bone formation. However, we could not confirm a more pronounced effect of dual inhibition compared to single inhibition.

Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS), a prevalent urological ailment, exerts a profound influence upon the well‐being of the males. Autoimmunity driven by Th17 cells has been postulated as a potential factor in CP/CPPS pathogenesis. Nonetheless, elucidating the precise mechanisms governing Th17 cell recruitment to the prostate, triggering inflammation, remained an urgent inquiry. This study illuminated that CCL20 played a pivotal role in attracting Th17 cells to the prostate, thereby contributing to prostatitis development. Furthermore, it identified prostate stromal cells and immune cells as likely sources of CCL20. Additionally, this research unveiled that IL‐17A, released by Th17 cells, could stimulate macrophages to produce CCL20 through the NF‐κB/MAPK/PI3K pathway. The interplay between IL‐17A and CCL20 establishes a positive feedback loop, which might serve as a critical mechanism underpinning the development of chronic prostatitis, thus adding complexity to its treatment challenges.

Objective Increased angiogenesis is a pathological feature of psoriasis, but the pathomechanisms of angiogenesis in psoriasis are not clear. Interleukin‐17A (IL‐17A) is the major effect factor in the pathogenesis of psoriasis. Our results showed that IL‐17A can promote angiogenesis and cause endothelial cell inflammation. Autophagy plays an important role not only in regulating inflammation, but also in regulating angiogenesis. Whether angiogenesis in psoriasis is related to autophagy remains unclear. In this study, we treated human umbilical vein endothelial cells (HUVECs) with IL‐17A to simulate increased angiogenesis to study whether increased angiogenesis in psoriasis is related to autophagy. Methods and Results Our results showed that treatment of HUVECs with IL‐17A significantly increased angiogenesis and expression levels of mRNA for multiple proinflammatory cytokines (CCL20, IL‐8, CCL2, IL‐6, and IL‐1β) and, while decreasing intracellular levels of nitric oxide (NO) and NO synthase (NOS) activity. Moreover, IL‐17A inhibited autophagy as shown that IL‐17A significantly increased expression levels of LC3II and p62 proteins. Induction of autophagy ameliorated IL‐17A‐mediated inflammatory response and inhibited angiogenesis, accompanied by increased p‐AMPKα(Thr172) and p‐ULK1(Ser555) expression, and decreased p‐mTOR(Ser2448) and p‐ULK1(Ser757) expression. Furthermore, inhibition of either AMPK or lysosomal acidification completely overrode autophagy‐induced changes in angiogenesis and NOS activity. Finally, induction of autophagy decreased apoptosis and caspase‐3 activity in IL‐17A‐treated HUVECs. Conclusions These results showed that IL‐17A is involved in angiogenesis and inflammatory response by inhibiting autophagy through AMPK signaling pathway, suggesting that autophagy may be a new therapeutic target for psoriasis.

Objective To investigate the effects of secukinumab treatment for psoriasis on different functional cytokines and inflammatory mediators in patients’ serum Methods Enzyme‐linked immunosorbent assay was used to detect interleukin (IL)‐1β and IL‐1RA associated with intrinsic immunity; IL‐6, IL‐18, and growth regulated oncogene alpha (GROα) associated with neutrophils; IL‐12, tumour necrosis factor (TNF)‐α, and interferon (IFN)‐γ associated with Th1; IL‐23, IL‐17A, and IL‐22 associated with Th17; Thymus activation regulated chemokine (TARC), IL‐13, and defensin beta 2 (DEFB2) associated with Th2; Vascular endothelial growth factor (VEGF)‐A and IL‐10 associated with angiogenesis; and IFN‐γ associated with sepsis in the peripheral blood of 12 patients with common psoriasis treated with secukinumab and 15 healthy controls. IL‐23, IL‐17A, IL‐22 associated with Th17; TARC, IL‐13, DEFB2 associated with Th2; VEGF‐A, IL‐10 associated with angiogenesis and procalcitonin (PCT) associated with sepsis. The differences in expression of the above cytokines before and after treatment and the correlation with psoriasis disease severity［Psoriasis Area Severity Index(PASI) score］, age, and disease duration were analyzed. Results The mean PASI score of the enrolled patients with moderate to severe psoriasis was 21.6 ± 11.0 before treatment and decreased to below 1 after treatment. Serum IL‐6; IL‐18, GROα, IFN‐γ, TNF‐α, VEGF‐A, and IL‐17A were significantly higher than normal. And IL‐17A and IFN‐γ were positively correlated with disease duration and age, and IL‐18 was positively correlated with PASI score. The expression levels of IL‐6, GROα, VEGF‐A, IFN‐γ, TNF‐α, IL‐17A and IL‐23 were significantly lower after secukinumab treatment compared with those before treatment, but the expression levels of IFN‐γ, VEGF‐A, TARC, IL‐13, and DEFB2 were still significantly higher than those of normal subjects after treatment Conclusions secukinumab clears skin lesions by antagonizing IL‐17A and simultaneously decreasing the expression levels of IL‐6, GRO α, VEGF‐A, IFN‐γ, TNF‐α, IL‐17A, and IL‐23.

Background T helper (Th) cells regulate immunity and inflammation to engage in cognitive impairment in several neurological diseases, while their clinical relevance in stroke patients is not clear. The current study intended to assess the relationship of Th1 cells, Th17 cells, interferon‐gamma (IFN‐γ), and interleukin (IL)‐17A with cognitive function in stroke patients. Methods One hundred twenty stroke patients and 40 controls were enrolled in this muticenter study. Th1 and Th17 cells in peripheral blood were assessed by flow cytometry; meanwhile, IFN‐γ and IL‐17A in serum were detected by enzyme‐linked immunosorbent assay. Cognitive function of stroke patients was evaluated by Mini‐Mental State Examination (MMSE) score at enrollment (baseline), year 1, year 2, and year 3. Results Th1 cells (p = 0.037) and IFN‐γ (p = 0.048) were slightly increased, while Th17 cells (p < 0.001) and IL‐17A (p < 0.001) were greatly elevated in stroke patients compared with controls. Th17 cells (rs = −0.374, p < 0.001) and IL‐17A (rs = −0.267, p = 0.003) were negatively correlated with MMSE score at baseline, but Th1 cells and IFN‐γ were not. Meanwhile, Th17 cells (p = 0.001) and IL‐17A (p = 0.024) were increased in patients with cognitive impairment compared to those without cognitive impairment. Notably, Th17 cells were positively associated with 1‐year (rs = 0.331, p < 0.001), 2‐year (rs = 0.261, p = 0.006), and 3‐year (rs = 0.256, p = 0.011) MMSE decline; IL‐17A was positively correlated with 1‐year (rs = 0.262, p = 0.005), 2‐year (rs = 0.193, p = 0.045), but not 3‐year MMSE decline. However, both Th1 cells and IFN‐γ were not linked with MMSE decline. Conclusion Th17 cells and IL‐17A estimate the progression of cognitive impairment in stroke patients. Totally 120 stroke patients and 40 controls were enrolled in this muticenter study. Then Th1 and Th17 cells in peripheral blood, IFN‐γ and IL‐17A in serum, were detected. Stroke patients were followed up for 3 years to evaluate the MMSE score. Th1 cells (p = 0.037) and IFN‐γ (p = 0.048) were slightly increased, while Th17 cells (p < 0.001) and IL‐17A (p < 0.001) were greatly elevated in stroke patients vs. controls. Th17 cells (p < 0.001) and IL‐17A (p = 0.003) were negatively correlated with MMSE score at baseline, but Th1 cells and IFN‐γ were not. Meanwhile, Th17 cells (p = 0.001) and IL‐17A (p = 0.024) were increased in patients with cognitive impairment vs. those without cognitive impairment. Notably, Th17 cells were positively associated with 1‐year (p < 0.001), 2‐year (p = 0.006) and 3‐year (p = 0.011) MMSE decline; IL‐17A was positively correlated with 1‐year (p = 0.005), 2‐year (p = 0.045), but not 3‐year MMSE decline. However, both Th1 cells and IFN‐γ were not linked with MMSE decline. Conclusively, Th17 cells and IL‐17A estimate the progression of cognitive impairment in stroke patients.

Plaque psoriasis is a chronic, recurrent, immune-mediated inflammatory skin disease. This study aimed to investigate effectiveness of interleukin (IL)-17A inhibitor treatment and effectiveness after treatment interruption in plaque psoriasis patients and analyze the related factors. This study retrospectively collected clinical characteristics and related treatment status of plaque psoriasis patients treated with IL-17A inhibitors, and evaluated the treatment effectiveness, reasons for treatment interruption, effectiveness after treatment interruption, and risk factors affecting treatment effectiveness. This study ultimately included 106 patients with plaque psoriasis, including 61 males (57.55%) and 45 females (42.45%), aged 41.0 (31.0-54.0) years and with a disease duration of 12.0 (8.0-20.0) months. Among them, 71 cases (67%) achieved PASI90 after receiving IL-17A inhibitor treatment, and 35 cases (33.02%) achieved PASI75. A total of 50 patients (50/106, 47.17%) interrupted treatment, 23 patients (23/50, 46%) maintained a therapeutic effect of PASI90 or above, and 27 patients (27/50, 54%) had a therapeutic effect lower than PASI75, with median time of treatment interruption of 1.0 (1.0-3.5) months. Univariate analysis findings showed that duration of IL-17A inhibitor treatment interruption and reasons for interruption had significant statistical significance on treatment effectiveness (all P<0.05). In multivariate analysis, treatment interruption (OR=7.154, 95% CI: 2.528-20.24) and reasons such as stress/anxiety (OR: 14.889, 95% CI: 1.160-23.480) were risk factors affecting treatment effectiveness. Interleukin (IL)-17A inhibitor treatment interruption plays critical effects on the treatment of plaque psoriasis. Early and long-term adherence to IL-17A inhibitor treatment can control the course of the disease and improve the long-term health of psoriasis patients.