IL-13 Receptor α1 Differentially Regulates Aeroallergen-Induced Lung Responses

Abstract

Interleukin (IL)-13 and IL-4 are hallmark cytokines of Th2-associated diseases including asthma. Recent studies revealed that IL-13Rα1 regulates asthma pathogenesis by mediating both IL-4 and IL-13-mediated responses. Nonetheless, the relative contribution of each cytokine in response to aeroallergen challenge and the degree of functional dichotomy between IL-4 and IL-13 in asthma remains unclear. Consistent with prior publications, we demonstrate that IL-13Rα1 regulates aeroallergen-induced airway resistance and mucus production but not IgE and Th2 cytokine production. We demonstrate that aeroallergen-induced eosinophil recruitment and chemokine production were largely dependent of IL-13Rα1 following Aspergillus (Asp) but not house dust mite (HDM) challenges. Notably, Asp-challenged mice displayed increased IL-13Rα1-dependent accumulation of dendritic cell subsets into lung draining lymph nodes in comparison with HDM. Comparison of IL-4 and IL-13 levels in the different experimental models revealed increased IL-4:IL-13 ratios following HDM challenge, likely explaining the IL-13Rα1-independent eosinophilia and chemokine production. Consistently, eosinophil adoptive-transfer experiments revealed near ablation of lung eosinophilia in response to Asp in Il13ra1−/− mice, suggesting that Asp-induced lung eosinophil recruitment is regulated by IL-13-induced chemokine production, rather than altered IL-13 signaling in eosinophils. Furthermore, the near complete protection observed in Il13ra1−/− mice in response to Asp-challenge was dependent on mucosal sensitization since Alum/Asp-sensitized mice that were re-challenged with Asp developed IL-13Rα1-independent eosinophilia although other asthma parameters remained IL-13Rα1-dependent. These results establish that IL-13Rα1 is required for aeroallergen-induced airway resistance and that allergen-induced chemokine production and consequent eosinophilia is dictated by the balance between IL-4 and IL-13 production in situ.

Resistin-Like Molecule–α Regulates IL-13–Induced Chemokine Production but Not Allergen-Induced Airway Responses

“…We demonstrate that IL-13Ra1 predominantly regulates increased Relm-a expression after Aspergillus fumigatus (Asp) allergen challenge, whereas after chicken egg ovalbumin (OVA) challenge, both IL-13Ra1 and probably Type I IL-4R contribute to the regulation of Relm-a expression. These findings were likely explained by the different sources of Relm-a expression and relatively higher IL-13/IL-4 ratio that was observed in the Asp model (14), suggesting that IL-13 directly induced Relm-a in lung epithelial cells and macrophages in vivo via the Type II IL-4R. Surprisingly, Relm-a was largely dispensable in the allergen-induced production of Th2 chemokines, cytokines, mucus production, and eosinophilia.…”

“…The differing cellular sources of Relm-a after exposure to these two allergens are likely explained by the differential IL-4R requirement and the relative induction of IL-4 and IL-13 in response to distinct allergens (14). Indeed, increased IL-13 concentrations will promote a predominant Type II IL-4R-dependent response pathway because IL-13-induced Relm-a expression mainly occurs in epithelial cells.…”

“…Indeed, we demonstrate that after allergen challenge, Relm-a is expressed by both airway epithelial cells and macrophages. Therefore, the differential regulation and expression of Relm-a are likely driven by the marked differences between the OVA 1 alum and Asp models and may result from differential IL-4 versus IL-13 production (14), as the ratio between IL-13 and IL-4 is substantially higher after Asp inoculation than after OVA inoculation (13,14). Despite our finding that lung eosinophils express Relm-a mRNA and that gastrointestinal eosinophils express Relm-a protein, murine eosinophils did not express Relm-a protein after IL-13 challenge or allergen challenge.…”

“…IL-4 can also use the Type II IL-4R, comprised of IL-4Ra and the IL-13 receptor-a1 chain (IL13Ra1) (9-11), a receptor complex that is also the cognate functional receptor for IL-13 (11). Recent analyses of Il13ra1 2/2 mice demonstrated an essential role for this receptor in mediating the effects of IL-13 and allergen in the lungs (12)(13)(14).…”

“…IL-4 can also use the Type II IL-4R, comprised of IL-4Ra and the IL-13 receptor-a1 chain (IL13Ra1) (9-11), a receptor complex that is also the cognate functional receptor for IL-13 (11). Recent analyses of Il13ra1 2/2 mice demonstrated an essential role for this receptor in mediating the effects of IL-13 and allergen in the lungs (12)(13)(14).Resistin-like molecule-a (Relm-a) belongs to a family of resistinlike molecules (Relms) including Relm-a, Relm-b, and Relm-g that are potent innate immune-modulating molecules (15). Interestingly, Relm-a and Relm-b expression is tightly regulated by IL-13, IL-4, and signal transducer and activator of transcription protein-6 (16-18).…”