CpG-ODNs and Budesonide Act Synergistically to Improve Allergic Responses in Combined Allergic Rhinitis and Asthma Syndrome Induced by Chronic Exposure to Ovalbumin by Modulating the TSLP-DC-OX40L Axis

Abstract

The experimental model of combined allergic rhinitis and asthma syndrome (CARAS) has shown that CpG oligodeoxynucleotides (CpG-ODNs) are potential inhibitors of type 2 helper cell-driven inflammatory responses. Currently available CpG-ODNs modestly inhibit allergic responses in CARAS, while a combination strategy for upper airway treatment by co-administration of CpG-ODNs and glucocorticoids may show good efficacy. This study aimed to assess the therapeutic effects of CpG-ODNs combined with budesonide (BUD) on upper and lower-airway inflammation and remodeling in mice with CARAS induced by chronic exposure to ovalbumin (OVA), exploring the possible underlying molecular mechanisms. A BALB/c mouse model of chronic CARAS was established by systemic sensitization and repeated challenge with OVA. Treatment with CpG-ODNs or BUD by intranasal administration was started 1 h after OVA challenge. Then, nasal mucosa and lung tissues were fixed and stained for pathologic analysis. The resulting immunologic variables and TSLP-DC-OX40L axis parameters were evaluated. Both CpG-ODNs and BUD intranasal administration are effective on reducing Th2-type airway inflammation and tissue remodeling. Co-administration of CpG-ODNs and BUD was more effective than each monotherapy in attenuating upper and lower-airway inflammation as well as airway remodeling in chronic CARAS. Notably, combination of CpG-ODNs with BUD modulated the TSLP-DC-OX40L axis, as demonstrated by decreased TSLP production in the nose and lung, alongside decreased TSLPR and OX40L in DC. Intranasal co-administration of CpG-ODNs and BUD synergistically alleviates airway inflammation and tissue remodeling in experimental chronic CARAS, through shared cellular pathways, as a potent antagonist of the TSLP-DC-OX40L axis.

IL‐37 alleviates house dust mite‐induced chronic allergic asthma by targeting TSLP through the NF‐κB and ERK1/2 signaling pathways

“…Allergic rhinitis and asthma coexist in a large proportion of patients. By establishing an experimental model of combined allergic rhinitis and asthma syndrome, we detected high TSLP level in both the upper and lower airways of mice exposed to allergen and identified TSLP as a key molecule for atopic march progression . One recent research study about skin lesions from Behçet's disease patients reported that IL‐37 as a suppressor of TSLP‐skin synthesis alleviated inflammatory effect of TSLP .…”

Intranasal Application of Budesonide Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Suppressing Nucleotide-Binding Oligomerization Domain-Like Receptor Family, Pyrin Domain-Containing 3 Inflammasome Activation in Mice

“…Second, the dose of budesonide given in this study was 0.5 mg/kg, which was higher than the dose of inhaled budesonide used in clinical practice [45]. The dose of budesonide was chosen based on our preliminary experimental data and other reports [23]. The higher dose of budesonide may be necessary owing to the intranasal delivery and species variations.…”

“…To study the effects of budesonide, mice with LPS-induced ALI were administered with intranasal administration of 50 μ L of budesonide (0.5 mg/kg) 1 h before LPS injection. This dose was chosen based on our own preliminary data and other previous studies [23, 24]. The mice were sacrificed at 12 h after LPS injection.…”

Yupingfeng Granule Improves Th2-Biased Immune State in Microenvironment of Hepatocellular Carcinoma through TSLP-DC-OX40L Pathway

“…T lymphocytes were obtained from C57/BL6 mice using the lymphocyte separation medium (Ficoll-Paque PLUS, GE, MA, USA). e stimulated DCs and T cells were cocultured in 6-well flatbottom plates at a ratio of 1 : 10 in the RPMI-1640 medium with 10% FBS as described previously [25]. e different concentrations of YPF were added in the mixed lymphocyte for 48 h. e collected cells were detected by flow cytometry for CD4 and IL-13 (eBioscience, Grand Island, NY, USA).…”

“…As TSLP is a potent activator of DCs [25], we evaluate whether YPF improves the mature states of DCs induced by TSLP. First, cell-surface receptors of DCs are required for T-cell activation [29].…”