Interleukin-17A (IL-17A) levels are elevated in patients with asthma. Ferroptosis has been identified as the non-apoptotic cell death type associated with asthma. Data regarding the relation of ferroptosis with asthma and the effect of IL-17A on modulating ferroptosis in asthma remain largely unclear. The present work focused on investigating the role of IL-17A in allergic asthma-related ferroptosis and its associated molecular mechanisms using public datasets, clinical samples, human bronchial epithelial cells, and an allergic asthma mouse model. We found that IL-17A was significantly upregulated within serum in asthma cases. Adding IL-17A significantly increased ferroptosis within human bronchial epithelial cells (BEAS-2B). In ovalbumin (OVA)-induced allergic asthmatic mice, IL-17A regulated and activated lipid peroxidation induced ferroptosis, whereas IL-17A knockdown effectively inhibited ferroptosis in vivo by protection of airway epithelial cells via the xCT-GSH-GPX4 antioxidant system and reduced airway inflammation. Mouse mRNA sequencing results indicated that the tumor necrosis factor (TNF) pathway was the differential KEGG pathway in the OVA group compared to healthy controls and the OVA group compared to the IL-17A knockout OVA group. We further used N-acetylcysteine (TNF inhibitor) to inhibit the TNF signaling pathway, which was found to protect BEAS-2B cells from IL-17A induced lipid peroxidation and ferroptosis damage. Our findings reveal a novel mechanism for the suppression of ferroptosis in airway epithelial cells, which may represent a new strategy for the use of IL-17A inhibitors against allergic asthma.

Fructooligosaccharides (FOS) can change gut microbiota composition and play a protective role in food allergy (FA). Furthermore, the protective mechanism of FOS against FA is unclear. In this study, intestinal flora and tryptophan (Trp) metabolites were investigated in a mouse model with FA supplemented with FOS. Meanwhile, we injected aryl hydrocarbon receptor antagonists (AhR-A) into a mouse model of FA supplemented with FOS to investigate whether T helper cell (Th) 17/regulatory T (Treg) cell balance was affected. Our research studies showed that dietary intake of FOS provided moderate protection from the intestinal inflammation induced by ovalbumin (OVA). This protective effect disappeared in AhR-A mice. The OVA mice manifestations had significantly lower bacterial richness, when compared to the normal control (NC) mice. Among fecal bacteria, the abundance of Akkermansiaceae (family level) and Verrucomicrobia (phylum level) increased and Ruminococcacere (phylum level) decreased in the feces of allergic mice. These changes were reversed by FOS treatment. FOS modulated the gut microbiome profiles that were altered in OVA mice, which showed an increase in the abundance of Ruminococcacere (phylum level) and a decrease in the abundance of Akkermansiaceae (family level) and Verrucomicrobia (phylum level). Liquid chromatography/tandem mass spectrometry (LC-MS/MS) analysis of Trp metabolites showed significant reductions in the level of kynurenine (kyn) in the serum of OVA mice, as compared to NC and FOS mice. Conversely, the levels of Trp and 5-hydroxytryptamine (5-HT) were significantly increased in OVA mice. Correlation analysis revealed a negative relationship between the relative abundance of Verrucomicrobiae (class level) and Akkermansiaceae (family level) with kyn, and a positive relationship with 5-HT. FOS significantly reduced interleukin-17A (IL-17A) and retinoic acid-associated nuclear orphan receptor-γt (RORγt) in FOS mice but not in AhR-A mice. FOS increased the level of interleukin-10 (IL-10) and Forkhead box P3 (Foxp3) in FOS mice but not in AhR-A mice. These findings suggest that FOS ameliorates allergic symptoms and impacts Th17/Treg balance in mice by modulating the gut microbiota composition and Trp metabolites. FOS may serve as an effective tool for the treatment of FA by regulating immune and gut microbiota.

Consumption of antibiotics is continuing to increase, with China accounting for approximately one quarter of the global intake. As a class of emerging environmental contaminants, antibiotics may pose a potential threat to human health, especially in children. However, the internal antibiotic exposure levels in pregnant women and their determinants remain unclear. Here we investigated the urinary creatinine-corrected concentration of 15 antibiotics in 762 pregnant women from the Shanghai Prenatal Cohort, by liquid chromatography-tandem mass spectrometry. Logistic regression analysis identified associations between high-antibiotic-level and maternal dietary factors. Results show that cumulatively antibiotics were detected at a frequency of 0.13 - 82.7%, with veterinary antibiotics (VAs) and preferred veterinary antibiotics (PVAs) detected in 76.9% and 98.2% of samples, respectively; PVAs were the most significant contributors to hazard index values > 1. Further, ciprofloxacin was the predominant antibiotic (median: 73.5 μg/mg creatinine), followed by norfloxacin (54.2 μg/mg creatinine); while sulfamethoxazole, enrofloxacin, and ciprofloxacin levels, used as a PVA or VA, were significantly higher in normal-weight and underweight women compared to overweight and obese women. Also, sulfamethoxazole, sulfadiazine, and ciprofloxacin were more frequently detected in mothers with a relatively low education degree. Interestingly, pregnant women with higher milk intake had a 1.96-times (95% CI: 1.10-3.49) greater risk of high-VA-exposure-level than the lower-intake group. The odds of exposure to high PVA, VA, PVA + VA, and all antibiotics levels for mothers with high egg consumption frequency were more than twice that of low-consumption individuals. Collectively, pregnant women in Shanghai are exposed to multiple environmental antibiotics, primarily as PVAs and VAs. Herein, we provide evidence for the association between dietary factors and maternal environmental antibiotic exposure in China. Special attention to antibiotic exposure and confirmation of potential determinants should be taken in the future.

Severe airway hyperresponsiveness (AHR) is a clinical feature of asthma, which has been associated with obesity and has shown a poor response to standard asthma treatments such as glucocorticoids. Numerous studies have shown that Interleukin (IL)-17 producing CD4+ T cells (Th17 cells), which could be inhibited by celastrol, is essential in mediating steroid-resistant AHR. The following study investigates the impact of celastrol and its mechanism on the regulation of AHR in murine model of obesity and asthma. C57BL/6 mice were sensitized by intraperitoneal injection of ovalbumin (OVA) on day 1 and 13 starting from 12th week, which was followed by aerosol OVA challenge that lasted for 30 min per daily for 7 consecutive days starting from 16th week. Diet-induced obesity (DIO) mice were fed a high fat diet (HFD) for 16 weeks. Celastrol was administrated orally for 7 consecutive days, 30 min before every challenge in DIO-OVA-induced mice. Lung functions were analyzed by measuring the airway resistance (Rn) and methacholine (MCh) AHR, while H&E staining was used to examine histological changes in the lungs. Immunohistochemistry was used to observe IL-17A protein in lung tissues; flow cytometry to detect the proportion of Th17 cells in CD4+T cells. The concentration of cytokines IL-17A in serum was assessed by standardized sandwich ELISA, while the expression of IL-17A mRNA in lung was examined by quantitative real-time RT-PCR. Briefly, our data indicated that celastrol reduced body mass in DIO-OVA-induced obesity and asthma. Both baseline Rn and MCh AHR were significantly lower in celastrol group. Moreover, celastrol treatment decreased the frequency of Th17 cell expansion and reduced the production of serum IL-17A. To sum up, our findings indicated that Th17 and its cytokine measured in the spleen and lung were closely associated with AHR. In addition, celastrol has shown the ability to suppress AHR through Th17 inhibition in obese asthmatic mice.

Introduction: The elevation of T helper (Th)17 cell frequencies and the imbalance of Th17/regulatory T (Treg) cells occur in asthma pathogenesis. Airway hyperresponsiveness (AHR) is a cardinal feature of asthma, and Th17 responses can promote AHR. We hypothesized that changes in Th17 cells and the Th17/Treg ratio correlate with AHR in asthmatic children. Methods: Twenty asthmatic children and twenty healthy children were included in the study. The peak expiratory flow (PEF) % pred, forced expiratory volume in 1 s (FEV₁) % pred and the FEV₁/forced vital capacity (FVC) ratio were measured in all subjects. Methacholine challenge test (MCT) was performed in asthmatic children. Flow cytometric analysis was used to determine the proportions of Th17 and Treg cells in peripheral blood mononuclear cells. ELISA was used to assess serum levels of interleukin (IL)-17A and IL-10. Results: Th17 cell frequencies (2.272 ± 0.207% in asthmatics, 1.193 ± 0.131% in controls, P＜0.01) and Th17/Treg ratios (0.371 ± 0.0387 in asthmatics, 0.183 ± 0.020 in controls, P＜0.01) were significantly increased in asthmatic children compared to controls. In asthmatic children, the MCT grade had positive correlations with the Th17 cell frequencies [r = 0.718, P＜0.01], serum IL-17A level [r = 0.753, P＜0.01] and Th17/Treg ratio [r = 0.721, P＜0.01], while the log₁₀PD20-FEV₁ value was negatively correlated with the Th17 cell frequencies [r=-0.654, P＜0.01], serum IL-17A level [r=-0.652, P＜0.01] and Th17/Treg ratio [r=-0.625, P＜0.01]. Conclusion: Th17 cell, IL-17A and Th17/Treg ratio were positively correlated with AHR in asthmatic children. It may be helpful to monitor Th17 cells and the Th17/Treg ratio as indicators of AHR in clinical practice.