Intestinal epithelial cells regulate airway allergic inflammation through induction of IgA Abs and and IL-17A (175.9)

Abstract

Abstract IKKβ-NF-κB signaling controls a large number of biological processes via tissue-specific regulation of inflammatory and anti-inflammatory responses. Using a model of oral antigen sensitization and mice with cell-specific deletion of IKKβ, we addressed the contribution of intestinal epithelial cells (IECs) to regulatory crosstalk between distant mucosal sites of the gastrointestinal tract and the airways. Mice with localized alteration of IKKβ-NF-κB signaling in IECs (IKKβΔIEC) exhibited unaltered IgE, but enhanced Th1-associated IgG2a Abs and IgA responses after oral antigen sensitization in the presence of cholera toxin. Interestingly, these mice showed reduced lung inflammation and mucus production after nasal allergen challenge. This protection required oral sensitization and was associated with the presence of IgA in bronchoalveolar fluids and increased IL-17A in the lungs. When orally sensitized with the same regimen, mice with a generalized IKKβ deficiency in cells of the myeloid lineage (IKKβΔMye) also were protected against nasal allergen challenge. Distinct mechanisms contributed to protection in IKKβΔIEC and IKKβΔMye mice since airway hyper-responsiveness and lung inflammation were completely abolished in IKKβΔMye mice, which also showed no IgA in bronchoalveolar fluid and lower IL-17A in the lung than IKKβΔIEC mice. In summary, IKKβ in IECs is sufficient for shaping immune responses to ingested antigens, and subsequent responses to antigen exposure via the airways.