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Journal of Allergy and Clinical Immunology

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Defective STING expression potentiates IL-13 signaling in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps - 05/05/21

Doi : 10.1016/j.jaci.2020.12.623 
Hai Wang, MD, PhD a, Dan-Qing Hu, MD b, Qiao Xiao, MD a, Yi-Bo Liu, MD a, Jia Song, MD, PhD a, Yuxia Liang, MD c, d, Jian-Wen Ruan, MD a, Zhe-Zheng Wang, MD a, Jing-Xian Li, MD a, Li Pan, MD, PhD a, Meng-Chen Wang, BS a, Ming Zeng, MD, PhD a, Li-Li Shi, MD, PhD a, Kai Xu, MD, PhD a, Qin Ning, MD, PhD b, Guohua Zhen, MD, PhD c, d, Di Yu, PhD e, De-Yun Wang, MD, PhD f, Sally E. Wenzel, MD g, Zheng Liu, MD, PhD a, ⁎
a Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 
b Department of Infectious Disease, Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 
c Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 
d Key Laboratory of Respiratory Diseases of Ministry of Health, Wuhan, China 
e Department of Immunology and Infection Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia 
f Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 
g University of Pittsburgh Asthma Institute at University of Pittsburgh Medical Center, Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pa 

∗Corresponding author: Zheng Liu, MD, PhD, Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, P.R. China.Department of Otolaryngology-Head and Neck SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and Technology1095 Jiefang AvenueWuhan430030P.R. China

Abstract

Background

Stimulator of interferon genes (STING) activation favors effective innate immune responses against viral infections. Its role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unknown.

Objective

Our aim was to explore the expression, regulation, and function of STING in CRSwNP.

Methods

STING expression in sinonasal mucosal samples was analyzed by means of quantitative RT-PCR, immunohistochemistry, flow cytometry, and Western blotting. Regulation and function of STING expression were explored by using cultured primary human nasal epithelial cells (HNECs) and cells of the line BEAS-2B in vitro.

Results

STING expression was reduced in eosinophilic nasal polyps compared with that in noneosinophilic nasal polyps and control tissues. STING was predominantly expressed by epithelial cells in nasal tissue and was downregulated by IL-4 and IL-13 in a signal transducer and activator of transcription 6 (STAT6)-dependent manner. HNECs derived from eosinophilic polyps displayed compromised STING-dependent type I interferon production but heightened IL-13–induced STAT6 activation and CCL26 production as compared with HNECs from noneosinophilic polyps and control tissues, which were rescued by exogenous STING overexpression. Knocking down or overexpressing STING decreased or enhanced expression of suppressor of cytokine signaling 1 (SOCS1) in BEAS-2B cells, respectively, independent of the canonic STING pathway elements TBK1 and IRF3. Knocking down SOCS1 abolished the inhibitory effect of STING on IL-13 signaling in BEAS-2B cells. STING expression was positively correlated with SOCS1 expression but negatively correlated with CCL26 expression in nasal epithelial cells from patients with CRSwNP.

Conclusions

Reduced STING expression caused by the type 2 milieu not only impairs STING-dependent type I interferon production but also amplifies IL-13 signaling by decreasing SOCS1 expression in nasal epithelial cells in eosinophilic CRSwNP.

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Graphical abstract




Le texte complet de cet article est disponible en PDF.

Key words : Chemokine (C-C motif) ligand 26, interleukin 13, nasal polyp, stimulator of interferon genes, suppressor of cytokine signaling 1, signal transducer and activator of transcription 6

Abbreviations used : ALI, CCL, 2’3’-cGAMP, CRSwNP, HNEC, IRF3, KO, MPO, siRNA, si-STAT6, si-STING, SOCS1, STAT6, STING, TBK1, TLR


Plan


 Supported by the National Natural Science Foundation of China (grants 81630024 and 81920108011 [to Z.L.]), 81900925 [to J.S.], 81702687 [to K.X.], and 81670019 [to G.Z.]), the Natural Science Foundation of Hubei Province of China (grants 2017CFA016 [to Z.L.] and 2018CFB602 [to M.Z.]), and an Australian National Health and Medical Research Council Fellowship (GNT1085509) and Bellberry-Viertel Senior Medical Research Fellowship (to D.Y.).
 Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.


© 2020  American Academy of Allergy, Asthma & Immunology. Publié par Elsevier Masson SAS. Tous droits réservés.
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Vol 147 - N° 5

P. 1692-1703 - mai 2021 Retour au numéro
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