Abstract
Interleukin-13 (IL-13) drives symptoms in asthma with high levels of T-helper type 2 cells (Th2-cells). Since tight junctions (TJ) constitute the epithelial diffusion barrier, we investigated the effect of IL-13 on TJ in human tracheal epithelial cells. We observed that IL-13 increases paracellular permeability, changes claudin expression pattern and induces intracellular aggregation of the TJ proteins zonlua occludens protein 1, as well as claudins. Furthermore, IL-13 treatment increases expression of ubiquitin conjugating E2 enzyme UBE2Z. Co-localization and proximity ligation assays further showed that ubiquitin and the proteasomal marker PSMA5 co-localize with TJ proteins in IL-13 treated cells, showing that TJ proteins are ubiquitinated following IL-13 exposure. UBE2Z upregulation occurs within the first day after IL-13 exposure. Proteasomal aggregation of ubiquitinated TJ proteins starts three days after IL-13 exposure and transepithelial electrical resistance (TEER) decrease follows the time course of TJ-protein aggregation. Inhibition of JAK/STAT signaling abolishes IL-13 induced effects. Our data suggest that that IL-13 induces ubiquitination and proteasomal aggregation of TJ proteins via JAK/STAT dependent expression of UBE2Z, resulting in opening of TJs. This may contribute to barrier disturbances in pulmonary epithelia and lung damage of patients with inflammatory lung diseases.
Highlights
Asthma is a complex disease that involves environmental interactions, genetic risk factors and chronic airway inflammation
Exposure of Human primary tracheal epithelial cells (hTEpC) epithelia to 10 ng/mL IL-13 or IL-4 for the entire air-liquid interface (ALI) cultivation time resulted in a transepithelial electrical resistance (TEER) decrease (Figure 1A)
Inhibition of JAK/STAT signaling by Tofacitinib [32,33] or S-Ruxolitinib [34,35] attenuated IL-13 effects on TEER and paracellular permeability (Figure 1D,E)
Summary
Asthma is a complex disease that involves environmental interactions, genetic risk factors and chronic airway inflammation. Depending on the dominating inflammatory response, the endotypes can be grouped in those with low levels of T-helper type 2 cells (Th2-cells), the Th2 low endotype, and those with high Th2-cell levels, described as Th2 high endotype [2]. The latter subsumes allergic asthma phenotypes with mainly Th2 cell driven symptoms. Novel treatment strategies follow approaches, where IL-13 signaling is inhibited either by immuno-inhibition of IL-13 dependent receptor signaling [6] or by immuno-neutralization of IL-13 itself [6,7,8,9,10] Both strategies can improve asthma symptoms and reduce risk of exacerbations
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