XBP1 is required in Th2 polarization induction in airway allergy

Rationale: Th2 polarization plays a central role in the pathogenesis of allergic diseases such as airway allergy. The underlying mechanism is not fully understood yet. X-box-binding protein-1 (XBP1) can regulate immune cell activities upon exposing stressful events. The role of XBP1 in the development of Th2 polarization has not yet been explored. Methods: Mice carrying Xbp1-deficient CD4⁺ T cells were employed to observe the role of XBP1 in the induction of airway allergy. A cell culture model was established to evaluate the role of XBP1 in facilitating the Th2 lineage commitment. Results: We found that Xbp1 ablation in CD4⁺ T cells prevented induction of Th2 polarization in the mouse airway tract. XBP1 was indispensable in the Th2 lineage commitment. XBP1 mediated the effects of 3-methyl-4-nitrophenol (MNP) on facilitating inducing antigen-specific Th2 response in the airways. Exposure to MNP induced expression of XBP1 in CD4⁺ T cells. RhoA facilitated the binding between XBP1 and GATA3 in CD4⁺ T cells. XBP1 induced GATA3 phosphorylation to promote the Il4 gene transcription. Modulation of the RhoA/XBP1 axis mitigated experimental allergic response in the mouse airways. Conclusions: A potential therapeutic target, XBP1, was identified in this study. XBP1 was required in the development of skewed Th2 response in the airways. Inhibiting XBP1 alleviated Th2 polarization-related immune inflammation in the airways. The data suggest that inhibiting XBP1 has the translation potential for the treatment of airway allergy.