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Tobacco smoke exposure is a major environmental risk factor that facilitates the development and progression of asthma. Our previous study showed that CpG oligodeoxynucleotide (CpG-ODN) inhibits thymic stromal lymphopoietin (TSLP)-dendritic cells (DCs) to reduce Th2/Th17-related inflammatory response in smoke-related asthma. However, the mechanism underlying CpG-ODN -downregulated TSLP remains unclear. A combined house dust mite (HDM)/cigarette smoke extract (CSE) model was used to assess the effects of CpG-ODN on airway inflammation, Th2/Th17 immune response, and amount of IL-33/ST2 and TSLP in mice with smoke-related asthma induced by adoptive transfer of bone-marrow-derived dendritic cells (BMDCs) and in the cultured human bronchial epithelium (HBE) cells administered anti-ST2, HDM, and/or CSE. In vivo, compared to the HDM alone model, the combined HDM/CSE model had aggravated inflammatory responses, while CpG-ODN attenuated airway inflammation, airway collagen deposition, and goblet cell hyperplasia and reduced the levels of IL-33/ST2, TSLP, and Th2/Th17-cytokines in the combined model. In vitro, IL-33/ST2 pathway activation promoted TSLP production in HBE cells, which could be inhibited by CpG-ODN. CpG-ODN administration alleviated Th2/Th17 inflammatory response, decreased the infiltration of inflammatory cells into the airway, and improved the remodeling of smoke-related asthma. The underlying mechanism may be that CpG-ODN inhibits the TSLP-DCs pathway by downregulating the IL-33/ST2 axis. [ABSTRACT FROM AUTHOR]

Background: Cigarette 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. Methods: The 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. Results: CpG-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. Conclusions: CpG-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. [ABSTRACT FROM AUTHOR]