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Evidence that oncostatin M synergizes with IL-4 signaling to induce TSLP expression in chronic rhinosinusitis with nasal polyps - 04/05/23

Doi : 10.1016/j.jaci.2022.11.029 
Bao-Feng Wang, MD, PhD a, b, Ping-Ping Cao, MD, PhD c, , James E. Norton, MS a, Julie A. Poposki, MS a, Aiko I. Klingler, PhD a, Lydia A. Suh, BS a, Roderick Carter, BS a, Julia H. Huang, MS a, Junqin Bai, PhD a, Whitney W. Stevens, MD, PhD a, Bruce K. Tan, MD d, Anju T. Peters, MD a, d, Leslie C. Grammer, MD a, David B. Conley, MD d, Kevin C. Welch, MD d, Zheng Liu, MD, PhD b, Robert C. Kern, MD d, Atsushi Kato, PhD a, Robert P. Schleimer, PhD a, d,
a Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill 
b Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 
c Department of Otolaryngology-Head and Neck Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China 
d Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago, Ill 

Corresponding author: Ping-Ping Cao, MD, PhD, Department of Otolaryngology-Head and Neck Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, 168 Litang Road, Beijing, China.Department of Otolaryngology-Head and Neck SurgeryBeijing Tsinghua Changgung HospitalSchool of Clinical MedicineTsinghua University168 Litang RoadBeijingChina∗∗Robert P. Schleimer, PhD, Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron, Rm M318, Chicago, IL 60611.Division of Allergy and ImmunologyDepartment of MedicineNorthwestern University Feinberg School of Medicine240 E. HuronRm M318ChicagoIL60611

Abstract

Background

Oncostatin M (OSM) may promote type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) by inducing thymic stromal lymphopoietin (TSLP).

Objective

We sought to study the impact of OSM on TSLP synthesis and release from nasal epithelial cells (NECs).

Methods

OSM receptors, IL-4 receptors (IL-4R), and TSLP were evaluated in mucosal tissue and primary NECs from patients with CRSwNP by quantitative PCR and immunofluorescence. Air-liquid interface–cultured NECs were stimulated with cytokines, including OSM, and quantitative PCR, ELISA, Western blot, and flow cytometry were used to assess the expression of OSM receptors, IL-4R, and TSLP.

Results

Increased levels of OSM receptor β chain (OSMRβ), IL-4Rα, and TSLP were observed in nasal polyp tissues and primary epithelial cells from nasal polyps of patients with CRSwNP compared with control tissues or cells from control subjects. The level of expression of OSMRβ in tissue was correlated with levels of both IL-4Rα and TSLP. OSM stimulation of NECs increased the expression of OSMRβ and IL-4Rα. Stimulation with IL-4 plus OSM augmented the production of TSLP; the response was suppressed by a signal transducer and activator of transcription 6 inhibitor. Stimulation of NECs with IL-4 plus OSM increased the expression of proprotein convertase subtilisin/kexin 3, an enzyme that truncates and activates TSLP.

Conclusions

OSM increases the expression of IL-4Rα and synergizes with IL-4 to induce the synthesis and release of TSLP in NECs. Because the combination of IL-4 and OSM also augmented the expression of proprotein convertase subtilisin/kexin 3, these results suggest that OSM can induce both synthesis and posttranslational processing/activation of TSLP, promoting type 2 inflammation.

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Key words : OSM, OSMRβ, IL-4Rα, TSLP, chronic rhinosinusitis, nasal polyps, nasal epithelial cells, type 2–dominant inflammation

Abbreviations used : ALI, BMEM, CRS, CRSsNP, CRSwNP, DMSO, EREG, IL-4Rα, IL-13Rα1, IL-13Rα2, LIFR, NEC, NHBEC, NP, OSM, OSMRβ, PCSK3, STAT6, TSLP, UT


Mappa


 The first 2 authors contributed equally to the manuscript as co-first authors.
 This research was supported in part by grants from the National Institutes of Health (grant nos. KL2 TR001424, K23 AI141694, R01 AI104733, 24 U19 AI106683, and P01 145818), by grants from the Parker B. Francis Fellowship Foundation 25, by a HOPE American Partnership For Eosinophilic Disorders (APFED)/American Academy of Allergy, Asthma & Immunology Pilot Grant Award, by the Ernest S. Bazley Foundation, and by the National Natural Science Foundation of China (grant nos. 81800888 and 82171113).
 Disclosure of potential conflict of interest: W. W. Stevens served on an advisory board for GlaxoSmithKline. B. K. Tan reports personal fees from Sanofi Regeneron/Genzyme and OptiNose. A. T. Peters reports personal fees from Sanofi Regeneron and personal fees and grants from AstraZeneca. L. C. Grammer reports personal fees from Astellas Pharmaceuticals. R. C. Kern reports personal fees from Sanofi Regeneron, Novartis, Lyra Pharmaceutical, and Neurent. A. Kato reports consultant fees from Astellas Pharmaceuticals and a gift for his research from Lyra Therapeutics. R. P. Schleimer reports personal fees from Intersect ENT, Merck, GlaxoSmithKline, Sanofi Regeneron, AstraZeneca/Medimmune, Genentech, Actobio Therapeutics, Lyra Therapeutics, Astellas Pharmaceuticals, Allakos, Inc, and Otsuka, Inc, and receives royalties from Siglec-8 and Siglec-8 ligand–related patents licensed by Johns Hopkins to Allakos. The rest of the authors declare that they have no relevant conflicts of interest.


© 2023  American Academy of Allergy, Asthma & Immunology. Tutti i diritti riservati.
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