Concomitant suppression of TH2 and TH17 cell responses in allergic asthma by targeting retinoic acid receptor–related orphan receptor γt

Abstract

Background Allergic asthma is a heterogeneous chronic inflammatory disease of the airways with a massive infiltration of eosinophils or neutrophils mediated by allergen-specific TH2 and TH17 cells, respectively. Therefore successful treatment of allergic asthma will require suppression of both TH2 and TH17 cells. Objective We sought to investigate the role of the TH17 cell pathway in regulating TH2 cell responses in allergic asthma. Methods Allergic asthma was induced by intranasal challenge with proteinase allergens in C57BL/6, Il17a−/−Il17f−/−, and retinoic acid receptor–related orphan receptor γt (RORγt)gfp/gfp mice. A pharmacologic RORγt inhibitor was used to evaluate its preventive and therapeutic effects in allergic asthma. Characteristics of allergic airway inflammation were analyzed by using flow cytometry, histology, quantitative real-time PCR, and ELISA. Mixed bone marrow chimeric mice, fate mapping analysis, short hairpin RNA transduction, and in vitro T-cell differentiation were used for mechanistic studies. Results Mice deficient in IL-17A and IL-17F, as well as RORγt, exhibited a significant reduction not only in TH17 cell responses but also in TH2 cell responses in an animal model of allergic asthma. Similarly, mice treated with an RORγt inhibitor had significantly diminished TH17 and TH2 cell responses, leading to reduced neutrophil and eosinophil numbers in the airway. RORγt-deficient T cells were intrinsically defective in differentiating into TH2 cells and expressed increased levels of B-cell lymphoma 6 (Bcl6). Bcl6 knockdown resulted in a remarkable restoration of TH2 cell differentiation in RORγt- deficient T cells. Blockade of RORγt also significantly hampered the differentiation of human TH2 and TH17 cells from naive CD4+ T cells. Conclusion RORγt in T cells is required for optimal TH2 cell differentiation by suppressing Bcl6 expression; this finding suggests that targeting RORγt might be a promising approach for the treatment of allergic asthma by concomitantly suppressing TH17 and TH2 cell responses in the airway.

Changes of DNA methylation are associated with changes in lung function during adolescence

“…CpGs cg11316510 and cg09573852 on genes RARA (retinoic acid receptor alpha) and IKBKB (Inhibitor of Nuclear Factor Kappa B Kinase), respectively, were among the IOW-ALSPAC consistent CpGs but not on the list of IOW-BAMSE consistent CpGs. Their significant involvement in lung function, as well as lung function development and pulmonary diseases such as asthma and COPD indicated the potential importance of these two CpGs and their mapped genes [11,[61][62][63][64][65][66][67][68][69][70][71]. RARA is the predominant isotype of the retinoic acid receptor (RAR) identified in alveolar type II epithelial cells and components of the retinoic acid signaling pathway [63][64][65][66][67][68].…”

Targeting ST2 expressing activated regulatory T cells in Kras-mutant lung cancer

“…To induce allergic lung inflammation, we adopted an animal model of proteinase-induced allergic asthma induced by repeated intranasal challenge with fungal proteinase allergens, as previously described. 17 In brief, mice were anesthetized with isoflurane and challenged intranasally with 7 μg of proteinase from Aspergillus oryzae (Sigma-Aldrich) in 50 μL of PBS every other day for 6 times (days 0, 2, 4, 6, 8, and 10). A day after the last challenge, lungs were collected and mononuclear cells from lungs were stained for Tregs.…”

A Critical Regulation of Th17 Cell Responses and Autoimmune Neuro-Inflammation by Ginsenoside Rg3

“…It has also been delineated that natural ligands stemming from endogenous cholesterol metabolism can either promote or inhibit RORγt function by directly interacting with its binding sites [29]. Ursolic acid is one of the most well-characterized RORγt antagonists, which ameliorates EAE and allergic asthma [30,31]. Since Rg3 has a tetracyclic triterpenoid saponin structure [14], a homologue of the ursolic acid, Rg3 might belong to the specific RORγt antagonists as well.…”