Inhibition of soluble epoxide hydrolase relieves adipose inflammation via modulating M1/M2 macrophage polarization to alleviate airway inflammation and hyperresponsiveness in obese asthma.

Obesityincreasestheriskofasthma and tends to enhance the asthma severity, however, its mechanism is not fully elucidated. The expansion of adipose tissue in obesity is accompanied by the accumulation of adiposetissue macrophages (ATMs) that could contribute to alow-gradeinflammationstate. In this study, we researched the regulatory role of soluble epoxide hydrolase (sEH) on ATMs-mediated inflammation in obese asthma. A mouse model of obese asthma that induced by high-fat diet (HFD) feeding and Ovalbumin (OVA) sensitization was employed to investigate the effects of AUDA, a sEH inhibitor (sEHi), on airway inflammation, airway hyperresponsivenesss (AHR) and pulmonary pathological changes. In addition to alleviating the key features of asthma in obese mice, we confirmed that AUDA reduced the expression of pro-inflammatory factor, such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumornecrosisfactor-α (TNF-α) in adipose tissue and serum. Moreover, AUDA could remarkedly reduce Lipopolysaccharide (LPS)-elevated IL-1ß, IL-6 and TNF-α in RAW264.7 macrophage cells. Mechanistically, AUDA effectively reduced inflammation in adipose tissue, resulting in reduced systemic inflammation, by inhibiting M1-type macrophage polarization and promoting M2-type macrophage polarization. These processes were found to act through ERK1/2 signaling pathway. Herein, we proved that inhibition of sEH expression helped to mitigate multiple parameters of obese asthma by regulating the balance of M1/M2 macrophage polarization in adipose tissue.

Molecular mechanism of interleukin-17A regulating airway epithelial cell ferroptosis based on allergic asthma airway inflammation.

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.

Bioinformatics analysis of ferroptosis-related gene AKR1C3 as a potential biomarker of asthma and its identification in BEAS-2B cells.

Ferroptosis is a newly discovered type of cell death and has recently been shown to be associated with asthma. However, the relationship between them at the genetic level has not been elucidated via informatics analysis. In this study, bioinformatics analyses are conducted using asthma and ferroptosis datasets to identify candidate ferroptosis-related genes using the R software. Weighted gene co-expression network analysis is performed to identify co-expressed genes. Protein-protein interaction networks, the Kyoto encyclopedia of genes and genomes, and gene ontology enrichment analysis are used to identify the potential functions of the candidate genes. We experimentally validate the results of our analysis using small interfering RNAs and plasmids to silence and upregulate the expression of the candidate gene in human bronchial epithelial cells (BEAS-2B). The ferroptosis signature levels are examined. Bioinformatics analysis of the asthma dataset GDS4896 shows that the level of the aldo-keto reductase family 1 member C3 (AKR1C3) gene in the peripheral blood of patients with severe therapy-resistant asthma and controlled persistent mild asthma (MA) is significantly upregulated. The AUC values for asthma diagnosis and MA are 0.823 and 0.915, respectively. The diagnostic value of AKR1C3 is verified using the GSE64913 dataset. The gene module of AKR1C3 is evident in MA and functions through redox reactions and metabolic processes. Ferroptosis indicators are downregulated by the overexpression of AKR1C3 and upregulated by silencing AKR1C3. The ferroptosis-related gene AKR1C3 can be used as a diagnostic biomarker for asthma, particularly for MA, and regulates ferroptosis in BEAS-2B cells.

Allergen immunotherapy combined with Notch pathway inhibitors improves HDM-induced allergic airway inflammation and inhibits ILC2 activation.

Introduction: Group 2 innate lymphoid cells (ILC2s) play a crucial role in house dust mite (HDM)-induced allergic inflammation, and allergen immunotherapy (AIT) holds promise for treating the disease by reducing the frequency of ILC2s. Despite significant progress in AIT for allergic diseases, there remains a need to improve the control of allergic symptoms. Methods: We investigated the synergistic effect of the Notch signaling pathway and subcutaneous immunotherapy (SCIT) in treating allergic airway inflammation in mice and their impact on the ratio of ILC2s in lung tissues. This was achieved by establishing the HDM-induced airway allergic disorders (HAAD) model and SCIT model. Additionally, we conducted in vitro investigations into the effect of the Notch signaling pathway on the secretory function of activated ILC2s using fluorescence-activated cell sorting. Furthermore, we explored the coactivation of the Notch signaling pathway with SCIT in vitro by sorting ILC2s from the lung tissues of mice after SCIT modeling. Results: Previously, our group demonstrated that Notch signaling pathway inhibitors can reduce allergic airway inflammation in mice. Notch signaling induces lineage plasticity of mature ILC2s. In this study, we showed that AIT alleviates allergic airway inflammation and suppresses the frequency of ILC2s induced by HDM. Interestingly, AIT combined with a γ-secretase inhibitor (GSI), an inhibitor of the Notch signaling pathway, significantly inhibited the frequency of ILC2s, reduced airway inflammation, and suppressed Th2-type responses in a mouse model. Furthermore, lung ILC2s from HDM-challenged mice with or without AIT were treated with GSI in vitro, and we found that GSI dramatically reduced the secretion of type 2 inflammatory factors in ILC2s. Discussion: These findings suggest that Notch signaling pathway inhibitors can be used as adjuvant therapy for AIT and may hold potential treatment value in the cooperative control of allergic airway inflammation during early AIT.