Abstract
House dust mites (HDMs) induce allergic diseases such as asthma. Neutrophil apoptosis is an important process of innate immunity, and its dysregulation is associated with asthma. In this study, we examined the effects of HDM on constitutive apoptosis of normal and asthmatic neutrophils. Extract of Dermatophagoides pteronissinus (DP) inhibited neutrophil apoptosis, but Dermatophagoides farinae extract had no effect. Anti-apoptotic signaling mediated by DP involves in TLR4, Lyn, PI3K, Akt, ERK, and NF-κB in normal neutrophils. DP delayed cleavage of procaspase 9 and procaspase 3 and the decrease in Mcl-1 expression. Supernatant collected from DP-treated normal neutrophils inhibited the constitutive apoptosis of normal neutrophils, and S100A8 and S100A9 were identified as anti-apoptotic proteins in the supernatant. S100A8 and S100A9 transduced the anti-apoptotic signal via TLR4, Lyn, PI3K, Akt, ERK, and NF-κB. DP also suppressed asthmatic neutrophil apoptosis and induced secretion of S100A8 and S100A9, which delayed the constitutive apoptosis. The anti-apoptotic effects of DP, S100A8 and S100A9 in asthmatic neutrophils are associated with TLR4, Lyn, PI3K, Akt, ERK, and NF-κB. The concentrations of S100A8 and S100A9 were significantly elevated in asthmatic bronchoalveolar lavage fluid (BALF) when compared to normal BALF (p<0.01), but not in serum. S100A8 concentration in BALF was positively correlated with the number of BALF neutrophils and negatively correlated with FEV1(%). These findings improve our understanding of the role of HDM in regulation of neutrophil apoptosis in normal individuals and asthmatics and will enable elucidation of asthma pathogenesis.
Highlights
Asthma is an allergic disease characterized by airway obstruction, allergen-specific IgE and bronchial inflammation
To investigate the effects of House dust mites (HDMs) on neutrophil apoptosis, we first evaluated whether major allergens of HDM, Dermatophagoides pteronissinus (DP) and Dermatophagoides farinae (DF) alter the regulation of neutrophil apoptosis
We have shown than TLR4 functions as a pivotal receptor in the anti-apoptotic mechanism of DP in normal and asthmatic neutrophils (Figs 2 and 5)
Summary
Asthma is an allergic disease characterized by airway obstruction, allergen-specific IgE and bronchial inflammation. House dust mites (HDMs), which primarily consist of Dermatophagoides pteronissinus (DP) and Dermatophagoides farinae (DF), are heavily involved in asthma pathogenesis [1, 2]. HDM allergens trigger allergic inflammation via Toll-like receptor (TLR), C type lectin receptor, NOD-like receptor and proteinase-activated receptor signaling pathways, and TLR4 in the TLR signaling is important in HDM-induced asthma [3, 4]. Asthma is composed of neutrophilic and eosinophilic subtypes. Neutrophilic asthma is characterized by a persistence of airway neutrophilia and is responsible for approximately half of mild-to-moderate asthmatic subjects. Neutrophils are considered important pathogenic agents and a worthy target in asthma treatment [5, 7, 8]
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