Transcription Factors GATA-3 and RORγt Are Important for Determining the Phenotype of Allergic Airway Inflammation in a Murine Model of Asthma

Abstract

In refractory asthma, neutrophils, rather than eosinophils, often predominate in the airways. Neutrophilic airway inflammation appears to be resistant to steroids and may be related to the Th17, rather than the Th2, cytokine milieu. However, the role of GATA-3 and RORγt, transcription factors for Th2 and Th17 cell differentiation, respectively, in the pathogenesis of steroid-insensitive asthma remains unclear. To examine the effect of GATA-3– and RORγt-overexpression backgrounds on airway inflammation and steroid sensitivity, we generated two strains of transgenic mice overexpressing GATA-3 or RORγt. Mice were sensitized and challenged with OVA. Some OVA-sensitized/challenged mice were treated with dexamethasone, anti–IL-17 Ab, CXCR2 antagonist, or anti–IL-6R Ab to demonstrate their therapeutic effects on airway inflammation. Although Ag-specific airway inflammation and hyperresponsiveness were induced in each mouse, the phenotype of inflammation showed a distinct difference that was dependent upon the genotype. GATA-3–overexpressing mice exhibited steroid-sensitive eosinophilic inflammation with goblet cell hyperplasia and mucus hyperproduction under Th2-biased conditions, and RORγt-overexpressing mice developed steroid-insensitive neutrophilic inflammation under Th17-biased conditions. The levels of keratinocyte-derived chemokine, MIP-2, IL-6, and other neutrophil chemotaxis-related mediators were significantly elevated in OVA-exposed RORγt-overexpressing mice compared with wild-type mice. Interestingly, airway hyperresponsiveness accompanied by neutrophilic airway inflammation in RORγt-overexpressing mice was effectively suppressed by anti–IL-17 Ab, CXCR2 antagonist, or anti–IL-6R Ab administration. In conclusion, our results suggest that the expression levels of GATA-3 and RORγt may be important for determining the phenotype of asthmatic airway inflammation. Furthermore, blockade of the Th17-signaling pathway may be a treatment option for steroid-insensitive asthma.

IL-17A Promotes the Exacerbation of IL-33–Induced Airway Hyperresponsiveness by Enhancing Neutrophilic Inflammation via CXCR2 Signaling in Mice

“…It has been reported that this chemokine is upregulated in lung epithelial and endothelial cells during inflammation (49), suggesting that epithelial and endothelial cells might contribute to the production of CXCL5 enhanced by the cooperative action of IL-33 and IL-17A. It has been reported that Ag-induced AHR, neutrophilic inflammation, and ELR + CXC chemokine production, such as CXCL1 and CXCL2 in experimental asthmatic models associated with IL-17A using Th17 cell-reconstituted SCID and RORgt-tg mice, were steroid resistant (50,51). Consistent with these data, we found that dexamethasone failed to inhibit coadministration of IL-33-and IL-17A-induced AHR, neutrophilic inflammation, and ELR + CXC chemokine production, indicating that AHR and neutrophilic inflammation exacerbated by IL-33 and IL-17A were also steroid resistant.…”

MicroRNA-26a/-26b-COX-2-MIP-2 Loop Regulates Allergic Inflammation and Allergic Inflammation-promoted Enhanced Tumorigenic and Metastatic Potential of Cancer Cells

“…7A). The expression of MIP-2 is significantly elevated in ovalbumin-dependent mouse model of asthma (30). In allergic airway inflammation, the expression of MIP-2 is increased (31).…”

Enforced Expression of Gata3 in T Cells and Group 2 Innate Lymphoid Cells Increases Susceptibility to Allergic Airway Inflammation in Mice

“…Several other groups have generated Tg mice with overexpression of Gata3 and have consistently reported enhanced eosinophilic airway inflammation (33)(34)(35)(36). In chronic models that involve repeated allergen exposure, enforced Gata3 expression was associated with increased subepithelial fibrosis and airway smooth muscle hyperplasia (35).…”

“…These CD2-Gata3 Tg mice lacked Th1-mediated hypersensitivity responses and showed reduced differentiation or activity of the Th17 cell subset, and protection from autoimmune encephalomyelitis and rheumatoid arthritis (29,31,32). Overexpression of Gata3 in T cells has been associated with enhanced Th2 responses and eosinophilic airway inflammation in vivo (33)(34)(35)(36). However, effects of Gata3 overexpression on the ILC2 population in AAI remain unknown.…”