Abstract
BackgroundCigarette smoke (CS) exposure increases corticosteroid insensitive asthma related to increased Th17 phenotype, and new treatment strategies are needed for CS-associated asthma. Histone deacetylase 2 (HDAC2), found in the airway epithelium, is critical for ameliorating glucocorticoids insensitivity. We recently demonstrated the anti-inflammatory effects of CpG oligodeoxynucleotides (CpG-ODNs) on CS-exposure asthma. However, the effects of CpG-ODNs on HDAC2 expression and enzymatic activity remain unclear. This study aimed to assess whether CpG-ODNs protect against excessive Th17 immune responses in CS-induced asthma through HDAC2-dependent mechanisms and compared their effects with those of corticosteroids.MethodsThe effects of CpG-ODNs alone and in combination with budesonide (BUD) on airway inflammation and Th2/Th17-related airway immune responses were determined using an in vivo model of CS-induced asthma and in cultured bronchial epithelial (HBE) cells administered ovalbumin (OVA) and/or cigarette smoke extract (CSE). HDAC2 and retinoid-related orphan nuclear receptor γt (RORγt) expression were also assessed in mouse lung specimens and HBE cells.ResultsCpG-ODNs and BUD synergistically attenuated CS exposure asthmatic responses in vivo by modulating the influx of eosinophils and neutrophils, airway remodeling, Th2/Th17 associated cytokine and chemokine production, and airway hyperresponsiveness and blocking RORγt-mediated Th17 inflammation through induced HDAC2 expression/activity. In vitro, CpG-ODNs synergized with BUD to inhibit Th17 cytokine production in OVA- and CSE-challenged HBE cells while suppressing RORγt and increasing epithelial HDAC2 expression/activity.ConclusionsCpG-ODNs reversed CS-induced HDAC2 downregulation and enhanced the sensitivity of CS-exposed asthmatic mice and CSE-induced HBE cells to glucocorticoid treatment. This effect may be associated with HDAC2 restoration via RORγt/IL-17 pathway regulation, suggesting that CpG-ODNs are potential corticosteroid-sparing agents for use in CS-induced asthma with Th17-biased immune conditions.
Highlights
Asthma is an increasingly prevalent respiratory ailment that affects at least 300 million individuals worldwide, with approximately 345,000 deaths annually [1]
We previously demonstrated that Cigarette smoke (CS) exposure asthma was associated Th17 differentiation and budesonide (BUD) had limited effects on neutrophil infiltration in bronchoalveolar lavage fluid (BALF), which suggested CS exposure asthma may be relatively insensitive to glucocorticoids (GCs) [10]
A combined granulocyte inflammatory phenotype was confirmed as indicated by elevated Gr-1 and ECP immunohistochemical signals in the lungs, as well as marked expression of eotaxin 1 in BALF (Fig. 1c), which facilitates the recruitment of eosinophils and neutrophils [28]
Summary
Asthma is an increasingly prevalent respiratory ailment that affects at least 300 million individuals worldwide, with approximately 345,000 deaths annually [1]. Inhaled corticosteroids (ICSs) are the standard therapeutic option for asthma, individuals show various responses, and most severe asthma patients may be insensitive to steroid-mediated suppression [6]. We previously demonstrated that CS exposure asthma was associated Th17 differentiation and budesonide (BUD) had limited effects on neutrophil infiltration in bronchoalveolar lavage fluid (BALF), which suggested CS exposure asthma may be relatively insensitive to glucocorticoids (GCs) [10]. This finding could explain why asthma patients exposed to CS directly or passively may exhibit reduced responsiveness to steroids. This study aimed to assess whether CpGODNs protect against excessive Th17 immune responses in CS-induced asthma through HDAC2-dependent mechanisms and compared their effects with those of corticosteroids
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