Role of ILC2s as Potential Effector Cells of IL25-Mediated Type 2 Inflammation in Chronic Rhinosinusitis with Nasal Polyps in China

Qiuning Yu,1 Ruibiao Song,1 Yunpeng Ba,1 Junjie Geng,2 Xuyang Liu,3 Tingting Liang,4 Shaochi Wang,3 Yulin Zhao1 1Otorhinolaryngology Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 2Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 3The Clinical Systems Biology Laboratories, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 4Henan Key Laboratory of Natural Medicine Innovation and Transformation, Henan University, Kaifeng, Henan Province, 475004, People’s Republic of ChinaCorrespondence: Shaochi Wang, Email [email protected]; [email protected] Yulin Zhao, Email [email protected]: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by Th2-type inflammation and is associated with dysregulated interleukin-25 (IL-25) expression. Type II innate lymphoid cells (ILC2s), as potential effector cells of IL-25, may contribute to the pathogenesis of CRSwNP. However, their specific role in nasal polyp (NP) tissues, particularly in Chinese patients, remains insufficiently understood.Methods: Nasal polyp (NP) tissue and turbinate mucosa (TM) were collected from 37 Chinese CRSwNP patients undergoing surgery. TM samples from 7 patients with pituitary tumors were used as controls. IL-25 expression, Th2 cytokines, phosphorylated STAT3 (p-STAT3), and ILC2 levels were assessed via immunohistochemistry, flow cytometry, and ELISA. Isolated ILC2s from NP tissues were stimulated with IL-25, with or without limonin treatment, to evaluate downstream cytokine production and STAT3 activation.Results: Compared to control TM, both NPs and TM from CRSwNP patients showed elevated IL-25 expression. NP tissues exhibited increased p-STAT3 levels and overexpression of Th2 cytokines. ILC2s were significantly more abundant in NPs and TM of CRSwNP patients. Upon IL-25 stimulation, NP-derived ILC2s produced higher levels of IL-5 and IL-13, accompanied by enhanced STAT3 phosphorylation. Limonin treatment significantly reduced both STAT3 activation and Th2 cytokine production in IL-25-stimulated NP tissues.Conclusion: ILC2s function as key effector cells of IL-25 in CRSwNP, promoting type-2 inflammation via the STAT3 signaling pathway. Limonin attenuates this response and may serve as a promising therapeutic agent for CRSwNP by targeting IL-25/STAT3-driven ILC2 activation. Keywords: chronic sinusitis, nasal polyps, turbinate mucosa, interleukin-25, IL-25, group 2 innate lymphoid cells, ILC2s, STAT3 signaling pathway, limonin