Th17 cells and IL-17 participate in airway neutrophil infiltration characteristics in the pathogenesis of severe asthma. Methyl-CpG binding domain protein 2 (MBD2) expression increased in CD4+ T cells in peripheral blood samples of asthma patients. However, little is known about that epigenetic regulation of MBD2 in both immunological pathogenesis of experimental severe asthma and CD4+ T cell differentiation. Here, we established a neutrophil-predominant severe asthma model, which was characterized by airway hyperresponsiveness (AHR), BALF neutrophil granulocyte (NEU) increase, higher NEU and IL-17 protein levels, and more Th17 cell differentiation. In the model, MBD2 and IRF4 protein expression increased in the lung and spleen cells. Under overexpression or silencing of the MBD2 and IRF4 gene, the differentiation of Th17 cells and IL-17 secretion showed positive changes. IRF4 protein expression showed a positive change with overexpression or silencing of the MBD2 gene, whereas there was no significant difference in the expression of MBD2 under overexpression or silencing of the IRF4 gene. These data provide novel insights into epigenetic regulation of severe asthma.
Neutrophilic asthma (NA) is associated with a severe disease course and poor response to corticosteroids. The present study aimed to compare the effects of various concentrations of house dust mite (HDM) allergens, ovalbumin (OVA), the major egg allergen, and lipopolysaccharide (LPS) in combination on the onset of severe NA. Female C57BL/6 mice were grouped according to a random number table and intranasally sensitized with HDM/LPS/OVA extracts on days 0, 1 and 2 of the study. In group 1, mice received 50 µg HDM + 50 µg OVA + 15 µg LPS, mice in group 2 received 50 µg HDM + 100 µg OVA + 15 µg LPS, mice in group 3 received 100 µg HDM + 50 µg OVA + 15 µg LPS and those in group 4 received 100 µg HDM + 100 µg OVA + 15 µg LPS, while mice in the control group received saline only. The mice were then challenged by OVA solution with atomized excitation on days 14, 15, 18, 19 and 20 for 30 min each. Ethology, airway hyperresponsiveness (AHR), immune cell distributions in bronchoalveolar lavage fluid (BALF), and specific cytokines interleukin 17A (IL-17A) and IL-4 in serum were assessed. Histological examination of inflammation by hematoxylin and eosin staining and immunohistochemical assessment of neutrophils (NEU), eosinophils (EOS), IL-17A and IL-4 were also performed. Compared with the control group, the HDM/OVA/LPS-sensitized groups 1–4 had markedly increased BALF cells, serum interleukin IL-17A and IL-4, inflammatory cell infiltration, EOS as well as IL-17A and IL-4 by immunohistochemical staining (all P<0.05). Among the four HDM/OVA/LPS-sensitized groups, mice of group 4 had higher AHR, a significantly higher total cell number, NEU and EOS in BALF as well as significantly higher NEU and NEU/EOS ratios according to immunohistochemical staining when compared to groups 1–3 (P<0.05 for all). In conclusion, sensitization with 100 µg HDM + 100 µg OVA + 15 µg LPS successfully established a severe asthma model with a predominantly neutrophilic inflammatory phenotype.
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