Background Bronchial epithelial barrier leakiness and type 2 innate lymphoid cells (ILC2s) have been separately linked to asthma pathogenesis; however, the influence of ILC2s on the bronchial ...epithelial barrier has not been investigated previously. Objective We investigated the role of ILC2s in the regulation of bronchial epithelial tight junctions (TJs) and barrier function both in bronchial epithelial cells of asthmatic patients and healthy subjects and general innate lymphoid cell– and ILC2-deficient mice. Methods Cocultures of human ILC2s and bronchial epithelial cells were used to determine transepithelial electrical resistance, paracellular flux, and TJ mRNA and protein expressions. The effect of ILC2s on TJs was examined by using a murine model of IL-33–induced airway inflammation in wild-type, recombination-activating gene 2 (Rag2) −/− , Rag2 −/− Il2rg −/− , and Rorasg/sg mice undergoing bone marrow transplantation to analyze the in vivo relevance of barrier disruption by ILC2s. Results ILC2s significantly impaired the epithelial barrier, as demonstrated by reduced transepithelial electrical resistance and increased fluorescein isothiocyanate–dextran permeability in air-liquid interface cultures of human bronchial epithelial cells. This was in parallel to decreased mRNAs and disrupted protein expression of TJ proteins and was restored by neutralization of IL-13. Intranasal administration of recombinant IL-33 to wild-type and Rag2 −/− mice lacking T and B cells triggered TJ disruption, whereas Rag2 −/− Il2rg −/− and Rorasg/sg mice undergoing bone marrow transplantation that lack ILC2s did not show any barrier leakiness. Direct nasal administration of IL-13 was sufficient to induce deficiency in the TJ barrier in the bronchial epithelium of mice in vivo. Conclusion These data highlight an essential mechanism in asthma pathogenesis by demonstrating that ILC2s are responsible for bronchial epithelial TJ barrier leakiness through IL-13.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
...bronchial epithelial cells are at the forefront of tissue defense and the innate immune response, preventing invasion of tissues as a physical barrier. CpG-2006 stimulation remarkably restored the ...impaired TJ immunostaining of bronchial epithelial ALI cultures from asthmatic patients (Fig 2, B, and see Fig E5, B), which is consistent with the TER and FITC-dextran flux measurements shown above. ...improvement of the barrier in bronchial epithelial cells by CpG-2006 seems to be mediated by enhanced expression of TJ-related molecules and their appropriate distribution on cell-cell borders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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