Search

Asthma is a chronic airway inflammatory disease caused by multiple genetic and environmental factors. This study mainly sought to provide potential therapeutic targets and biomarkers for neutrophilic asthma (NA). Three gene expression profiling datasets were obtained from the Genome Expression Omnibus (GEO) database. GSE45111 and GSE41863 were used to identify hub genes and potential biomarkers, and GSE137268 was used for data verification. We verified the repeatability of intragroup data and identified differentially expressed genes (DEGs). Then, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the DEGs, and a protein–protein interaction (PPI) network was constructed to identify the hub genes. Finally, receiver operating characteristic (ROC) analysis was used to verify the ability of the hub genes to differentiate between NA and eosinophilic asthma (EA). In this study, we identified 411 DEGs by comprehensive analysis of NA/EA patients and NA/healthy controls (HCs). Ten hub genes (CXCR1, FCGR3B, CXCR2, SELL, S100A12, CSF3R, IL6R, JAK3, CD48, and GNG2) were identified from the PPI network. Finally, based on the ROC analysis, 7 genes showed good diagnostic value for discriminating NA from EA—CXCR1, FCGR3B, CXCR2, SELL, S100A12, CSF3R, and IL6R (AUC > 0.7). We identified 7 hub genes that can distinguish NA from EA. The IL-8-mediated signaling may be the primary pathway to determine the NA phenotype in asthma. CXCR1/2 and S100A12 may be the primary genes determining the NA phenotype. CXCR1/2 and S100A12 might be biomarkers and new therapeutic targets for NA. Supplemental data for this article is available online at at [ABSTRACT FROM AUTHOR]

Adenine modifications, including m6A, m1A, APA, and A‐to‐I modifications, are the most impactful RNA modifications. These modifications are primarily produced by enzymes called writers. The main purpose of this study was to explore the cross‐talk and potential roles of these writers in severe asthma. We found 13 RNA writers potentially related to severe asthma and three RNA modification patterns. Cluster 3 showed predominant neutrophil infiltration and C‐type lectin receptor signaling; cluster 1 showed predominant innate immune cell infiltration and ubiquitin–proteasome system activation; and cluster 2 did not show obvious immune infiltration characteristics. We found that RNA modification writers modified immune cell–related genes and led to both accumulation of different immune cells in the airways and activation of a series of biological processes, which ultimately leads to severe asthma. TRMT6, WTAP, and TRMT6A were included in a random forest model as predictors. Cromoglicic acid, thioperamide, and fluvastatin were potential drugs for clusters 1, 2, and 3, respectively. We found that cross‐talk of RNA modifications is significant in severe asthma, which provides insight into severe asthma pathogenesis and possible treatment avenues. [ABSTRACT FROM AUTHOR]

Our previous studies have showed that sulfatide-reactive type II NKT (i.e. variant NKT, vNKT) cells inhibit the immunogenic maturation during the development of mature lung dendritic cells (LDCs), leading todeclined allergic airway inflammation in asthma. Nonetheless, the specific immunoregulatory roles of vNKT cells in LDC-mediated Th2 cell responses remain incompletely understood. Herein, we found that administration of sulfatide facilitated the generation of CD4+FoxP3+ regulatory T (Treg) cells in the lungs of wild-type mice, but not in CD1d−/− and Jα18−/− mice, after ovalbumin or house dust mite exposure. This finding implies that the enhancement of lung Treg cells by sulfatide requires vNKT cells, which dependent on invariant NKT (iNKT) cells. Furthermore, the CD4+FoxP3+ Treg cells induced by sulfatide-reactive vNKT cells were found to be associated with PD-L1 molecules expressed on LDCs, and this association was dependent on iNKT cells. Collectively, our findings suggest that in asthma-mimicking murine models, sulfatide-reactive vNKT cells facilitate the generation of lung Treg cells through inducing tolerogenic properties in LDCs, and this process is dependent on the presence of lung iNKT cells. These results may provide a potential therapeutic approach to treat allergic asthma. [ABSTRACT FROM AUTHOR]

• Cellular senescence-related biological processes may be involved in the pathogenesis of severe asthma. • The expression of ETS2, ETS1 and AURKA were increased in the severe asthma. • Two distinct senescence subtypes were identified in severe asthma with distinct immune microenvironment and molecular biological characteristics. • The random forest predictive model based on PEBP1 and MDH1 has good accuracy in predicting senescence subtypes of severe asthma. • Bezafibrate, EBPC and felodipine may be the potential therapeutical drugs for Cluster 1, while FK-888, trimethobenzamide and PD-0325901 may be the potential therapeutical drugs for Cluster 2. Recent studies have shown that cellular senescence is involved in the pathogenesis of severe asthma (SA). The objective of this study was to investigate the role of cellular senescence-related genes (CSGs) in the pathogenesis of SA. Here, 54 differentially expressed CSGs were identified in SA patients compared to healthy control individuals. Among the 54 differentially expressed CSGs, 3 CSGs (ETS2, ETS1 and AURKA) were screened using the LASSO regression analysis and logistic regression analysis to establish the CSG-based prediction model to predict severe asthma. Moreover, we found that the protein expression levels of ETS2, ETS1 and AURKA were increased in the severe asthma mouse model. Then, two distinct senescence subtypes of SA with distinct immune microenvironments and molecular biological characteristics were identified. Cluster 1 was characterized by increased infiltration of immature dendritic cells, regulatory T cells, and other cells. Cluster 2 was characterized by increased infiltration levels of eosinophils, neutrophils, and other cells. The molecular biological characteristics of Cluster 1 included aerobic respiration and oxidative phosphorylation, whereas the molecular biological characteristics of Cluster 2 included activation of the immune response and immune receptor activity. Then, we established an Random Forest model to predict the senescence subtypes of SA to guide treatment. Finally, potential drugs were searched for each senescence subgroup of SA patients via the Connectivity Map database. A peroxisome proliferator-activated receptor agonist may be a potential therapeutic drug for patients in Cluster 1, whereas a tachykinin antagonist may be a potential therapeutic drug for patients in Cluster 2. In summary, CSGs are likely involved in the pathogenesis of SA, which may lead to new therapeutic options for SA patients. [ABSTRACT FROM AUTHOR]

Background: B cells were believed to act as antigen-presenting cells (APCs) to promote T helper type 2 (Th2) cell responses. However, the role of lung B cells and its subpopulations in Th2 cell responses in asthma remains unclear. Objective: We leveraged an anti-CD20 monoclonal antibody (mAb) treatment that has been shown to selectively deplete B cells in mice and investigated whether this treatment modulates Th2 cell responses and this modulation is related to lung follicular mature (FM) B cells in a murine model of asthma. Methods and results: We used a house dust mite (HDM)-induced asthma mouse model and found that anti-CD20 mAb treatment attenuates Th2 cell responses. Meanwhile, anti-CD20 mAb treatment did dramatically reduce the number of B cells, especially FM B cells in the lungs, but did not impact the frequency of other immune cell types, including lung T cells, dendritic cells, natural killer cells, and regulatory T cells in wild-type mice. Moreover, we found that the suppressive effect of anti-CD20 mAb treatment on Th2 cell responses could be reversed upon adoptive transfer of lung FM B cells, but not lung CD19+ B cells without FM B cells in asthmatic mice. Conclusions: These findings reveal that anti-CD20 mAb treatment alleviates Th2 cell responses, possibly by depleting lung FM B cells in a Th2-driven asthma model. This implies a potential therapeutic approach for asthma treatment through the targeting of lung FM B cells. [ABSTRACT FROM AUTHOR]

• Anti-CD1d treatment suppress Th2 cell responses in asthma by suppresses immunogenic maturation of LDCs. • Anti-CD1d treatment lowers the abundance and activation of lung iNKT cells in asthma. • The influences of anti-CD1d treatment in LDCs of asthma were dependent on lung iNKT cells. • The influences of anti-CD1d treatment in LDCs of asthma were relevant to the downregulation of CD40L expression on lung iNKT cells. Our previous findings show that invariant natural killer T (iNKT) cells can promote immunogenic maturation of lung dendritic cells (LDCs) to enhance Th2 cell responses in asthma. It has been accepted that recognition of glycolipid antigens presented by CD1d molecules by the T cell receptors of iNKT cells leads to iNKT cell activation. Therefore, we examine the immunoregulatory influences of anti-CD1d treatment on Th2 cell response and immunogenic maturation of LDCs and subsequently explored whether these influences were dependent on lung iNKT cells in asthmatic mice. We discovered that in wild-type mice sensitized and challenged with house dust mite or ovalbumin (OVA), anti-CD1d treatment inhibited Th2 cell response and immunogenic maturation of LDCs. LDCs from asthmatic mice with anti-CD1d treatment had a markedly decreased influence on Th2 cell responses in vivo and in vitro. Furthermore, anti-CD1d treatment reduced the abundance and activation of lung iNKT cells in asthmatic mice. Moreover, in asthmatic iNKT cell-deficient Jα18-/- mice, anti-CD1d treatment did not influence Th2 cell responses and immunogenic maturation of LDCs. Meanwhile, the quantity of CD40L+ iNKT cells in asthmatic mice was significant decreased by anti-CD1d treatment. Finally, the inhibition of anti-CD1d treatment on LDC immunogenic maturation and Th2 cell responses in asthmatic mice was reversed by anti-CD40 treatment. Our data suggest that anti-CD1d treatment can suppress Th2 cell responses through inhibiting immunogenic maturation of LDCs dependent on lung iNKT cells, which could be partially related to the downregulation of CD40L expression on lung iNKT cells in asthmatic mice. [ABSTRACT FROM AUTHOR]

Cutaneous malignant melanoma (CMM) is one of the most dangerous types of skin cancer. The prognosis of CMM patients with ulcers, regional lymph node metastasis or organ metastasis is poor. In this process, resistance to anoikis is a critical step in tumor cell metastasis. Tumor cells survive in the vascular and lymphatic system through the escape of anoikis to finally form clones in the distal tissue. The present study revealed that muscle intestine and stomach expression 1 (MIST1), a secreting cell-restricted transcription factor, was overexpressed in melanoma cells. At the same time, the expression of SNAI1 was also high. High expression of MIST1 and SNAI1 all contributed to melanoma cells bypassing anoikis. By changing the expression of MIST1, SNAI1 was indicated to be a downstream gene of MIST1. Chromatin immunoprecipitation and luciferase reporter gene technology revealed that MIST1 promoted the expression of SNAI1 by directly binding to its promoter region. Furthermore, inhibition of the phosphorylation/activity of Akt by LY294002 and knockdown of phosphatase and tensin homologue (PTEN) with simultaneous upregulation or knockdown of MIST1 revealed that SNAI1 improved the phosphorylation of Akt by inhibiting the expression of PTEN. These results suggested that MIST1 hijacked the PTEN/AKT signaling pathway through directly regulating SNAI1 and affected the anoikis resistance capacity of melanoma cells. [ABSTRACT FROM AUTHOR]

5-Fluorouracil (5-FU) is an analog of pyrimidine and has been shown to display antitumor and immunomodulatory effects. However, the impacts of 5-FU in regulating asthma, an inflammatory disease associated with T helper cell 2 (Th2) responses, remain unclear. Here, we determine the modulatory effects of low-dose 5-FU on Th2 cell responses in asthma and delineate the underlying mechanisms using adoptive cell transfer and in vitro culture experiments. Our data show that low-dose 5-FU treatment not only inhibits the induction of asthma in allergen-sensitized mice but also abrogates the major features of asthma in mice with established disease. We find that this protection of 5-FU treatment against asthma is accompanied by a decrease in the number of lung monocyte-derived dendritic cells (moDCs) in the asthmatic murine. Furthermore, we show that adoptive transfer of moDCs reverses the inhibitory effects of 5-FU treatment on Th2 cell responses in asthmatic mice. Surprisingly, 5-FU treatment does not suppress surface maturation markers and immunogenicity of moDCs in the lungs of asthmatic mice. Instead, it induces apoptotic cell death of mouse moDCs both in vitro and in vivo. In addition to its impact on mouse moDCs, we observe that low-dose 5-FU treatment can induce apoptotic cell death of human moDCs derived from peripheral blood mononuclear cells in vitro. Together, our findings reveal that low-dose 5-FU ameliorates Th2 cell responses, which may be at least partially related to the induction of apoptotic cell death of moDCs in asthma. [Display omitted] • Allergic asthma is driven by Th2 cell responses. • 5-Fluorouracil ameliorates Th2 cell responses in allergic asthma. • Monocyte-derived dendritic cells are critical in driving Th2 cell responses. • 5-Fluorouracil induces apoptotic cell death of monocyte-derived dendritic cells. [ABSTRACT FROM AUTHOR]

The article examines the effects of the interleukin (IL)-22 on the expression and proliferation of heparin-binding-epidermal growth factor (HB-EGF) in HaCaT keratinocytes. With IL-22, HaCaT cell proliferation is stimulated at different concentrations. The proliferation-inducing role of IL-22 is confirmed by knocking down its expression using small interfering RNA. A significant increase in HB-EGF messenger RNA (mRNA) and protein levels in HaCaT cells is also noted following IL-22 treatment.