Epithelium-derived kallistatin promotes CD4+ T-cell chemotaxis to TH2-type inflammation in chronic rhinosinusitis

Lijie Jiang; Haocheng Tang; Tengjiao Lin; Yifeng Jiang; Yanmei Li; Wenxiang Gao; Jie Deng; Zhaoqi Huang; Chuxin Chen; Jianbo Shi; Ti Zhou; Yinyan Lai

doi:10.1016/j.jaci.2024.02.013

Epithelium-derived kallistatin promotes CD4⁺ T-cell chemotaxis to T_H2-type inflammation in chronic rhinosinusitis

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

Authors

Lijie Jiang¹, Haocheng Tang², Tengjiao Lin³, Yifeng Jiang⁴, Yanmei Li⁵, Wenxiang Gao⁴, Jie Deng⁴, Zhaoqi Huang⁴, Chuxin Chen⁴, Jianbo Shi⁶, Ti Zhou⁷, Yinyan Lai⁸

Affiliations

¹ Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Otorhinolaryngology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
² Department of Otorhinolaryngology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
³ Department of Radiation Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
⁴ Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁵ Basic and Clinical Medicine Teaching Laboratory, School of Medicine, Sun Yat-sen University, Shenzhen, China.
⁶ Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: tsjbent@163.com.
⁷ Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; China Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China. Electronic address: zhouti2@mail.sysu.edu.cn.
⁸ Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: laiyy3@mail.sysu.edu.cn.

PMID: 38403085
DOI: 10.1016/j.jaci.2024.02.013

Abstract

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

Objective: We sought to investigate the role of kallistatin in airway inflammation.

Methods: Kallistatin and proinflammatory cytokine expression levels were detected in nasal polyps. For the in vivo studies, we constructed the kallistatin-overexpressing transgenic mice to elucidate the role of kallistatin in airway inflammation. Furthermore, the levels of plasma IgE and proinflammatory 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 CRSwNP.

Results: 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 mice expressed higher levels of IL-4 expression, associating to T_H2-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 allergen compared with the wild-type house dust mite 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 T_H2-type inflammation.

Conclusions: Kallistatin was demonstrated to be involved in the CRSwNP pathogenesis by enhancing the T_H2 inflammation, which was found to be associated with more expression of IL-4, potentially facilitated through Jagged2-Notch1 signaling in CD4⁺ T cells.

Keywords: Kallistatin; Notch; T(H)2-type inflammation; chronic rhinosinusitis with nasal polyps (CRSwNP).