Epithelium-derived kallistatin promotes CD4+ T cell chemotaxis to Th2-type inflammation in chronic rhinosinusitis

J Allergy Clin Immunol. 2024 Feb 23:S0091-6749(24)00193-3. doi: 10.1016/j.jaci.2024.02.013. Online ahead of print.

Abstract

Background: The function of kallistatin in airway inflammation, particularly chronic rhinosinusitis with nasal polyps (CRSwNP), has not been elucidated.

Objective: This study aimed to investigate the role of kallistatin in airway inflammation.

Methods: Kallistatin and pro-inflammatory cytokine expression levels were detected in nasal polyps. For the in vivo studies, we constructed the kallistatin overexpressing transgenic mice (TG) to elucidate the kallistatin's role in airway inflammation. Further, the levels of plasma immunoglobulin E (IgE) and pro-inflammatory cytokines in the airways were evaluated in the kallistatin-/- rat in vivo model under a type 2 inflammatory background. Finally, the Notch signaling pathway was explored to understand the role of kallistatin in the CRSwNP.

Results: Here, we showed that the expression of kallistatin was significantly higher in nasal polyps than in the normal nasal mucosa and correlated with IL-4 expression. We also discovered that the nasal mucosa of kallistatin overexpressing transgenic (TG) mice expressed higher levels of IL-4 expression, associating to Th2-type inflammation. Interestingly, we observed lower IL-4 levels in the nasal mucosa and lower total plasma IgE of the kallistatin-/- group treated with house dust mite (HDM) allergen compared with WT-HDM group. Finally, we observed a significant increase in the expression of jagged2 in the nasal epithelium cells transduced with adenovirus-kallistatin. This heightened expression correlated with increased secretion of IL-4, attributed to the augmented population of CD4+CD45+Notch1+ T cells. These findings collectively may contribute to the induction of Th2-type inflammation.

Conclusion: Kallistatin was demonstrated to be involved in the CRSwNP pathogenesis by enhancing the Th2 inflammation, which was found to be associated with more expression of IL-4, potentially facilitated through Jagged2-Notch1 signaling in CD4+ T cells.

Keywords: Chronic rhinosinusitis with nasal polyps (CRSwNP); Kallistatin; Notch; Th2-type inflammation.