Epithelial cytokine IL-33 and sub-epithelial matrix protein tenascin C compartmentalize eosinophil phenotype and function

Abstract

Abstract In allergic inflammation, eosinophils interacting with epithelial barriers experience exposure to epithelial cytokines and the extracellular milieu of airway remodeling. To better understand eosinophil activation biology in allergic tissue, we modeled the synergistic and opposing regulation of naïve eosinophils by both sub-epithelial extracellular matrix protein tenascin C (TNC), a key player in epithelial regeneration, and IL-33, an epithelial damage-induced cytokine. IL-5-differentiated bone marrow-derived murine eosinophils were cultured with recombinant TNC (25 ug/ml), IL-33 (100 ng/ml), or both for 24 hours and profiled by flow cytometry, qPCR, and DiffQuick staining. IL-33 alone significantly induced IL-4 and integrin CD11b expression, which was antagonized by co-culture with TNC. Conversely, TNC alone significantly promoted CD34 and intra-epithelial docking integrin CD103 expression, which was suppressed by IL-33 addition. Both treatments synergized in promoting expression of trans-epithelial migration marker CD11c. TNC promoted resident morphology while IL-33 induced an activated phenotype. This illustrates how microenvironmental cues may progressively shape eosinophils trafficking from sub-epithelial space across epithelial barriers.