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

Wang, Baofeng; Cao, Pingping; Norton, James E.; Poposki, Julie A.; Klingler, Aiko I.; Suh, Lydia; Carter, Roderick; Huang, Julia; Bai, Junqin; Stevens, Whitney W.; Tan, Bruce K.; Peters, Anju T.; Grammer, Leslie C.; Conley, David B.; Welch, Kevin C.; Liu, Zheng; Kern, Robert C.; Kato, Atsushi; Schleimer, Robert P.

doi:10.1016/j.jaci.2022.11.029

Cited by 7 publications

(3 citation statements)

References 47 publications

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“…As previously stated, CST1 expression is elevated in ECRS, while IL-17 can repress CST1 in neutrophilic inflammation [62]. OSM, product by active neutrophil, can increase the expression of IL-4 receptor a, and induced epithelium synthesis and release TSLP, enhancing the eosinophil inflammatory [83].…”

Section: Mixed Eosinophilic-neutrophilic Inflammation In Chronic Rhin...mentioning

confidence: 67%

Interaction of eosinophilic and neutrophilic inflammation in patients with chronic rhinosinusitis

Sima,

Wang,

Zhang

2023

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of review In the past year, the endotype of chronic rhinosinusitis (CRS) has been studied from a new perspective. Eosinophilic and neutrophilic inflammation are not independent processes in the pathogenesis of CRS. In this review, we will focus on recent research on mixed eosinophilic-neutrophilic inflammation in CRS and discuss the mechanism and potential treatments. Recent findings Traditionally, patients with eosinophilic CRS (ECRS) present with severe clinical manifestations, comorbidities, and a higher recurrence rate. Recent studies have found that approximately 40% of patients with ECRS present with neutrophilic infiltration, while patients with predominantly eosinophilic infiltration along with neutrophilic inflammation present with more complex inflammation, clinical manifestations and exhibit refractory characteristics. Summary The complex inflammatory profile and refractory clinical characteristics of mixed eosinophilic-neutrophilic inflammation in CRS are current challenges for clinicians. We summarize the features of eosinophilic and neutrophilic inflammation and current studies on the mechanisms of mixed eosinophilic-neutrophilic inflammation and suggest potentially effective therapeutic methods. We hope that this review will help with determining precise treatment options for patients.

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Section: Mixed Eosinophilic-neutrophilic Inflammation In Chronic Rhin...mentioning

confidence: 67%

Interaction of eosinophilic and neutrophilic inflammation in patients with chronic rhinosinusitis

Sima,

Wang,

Zhang

2023

Current Opinion in Allergy &Amp; Clinical Immunology

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“…IL-4R signaling drives mucous cell metaplasia, macrophage alternative activation, Th2 cell differentiation, and type 2 inflammation in allergic diseases (31)(32)(33)(34)(35)(36). However, the mechanism underlying the regulation of IL-4R expression remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Cadherin-26 drives macrophage alternative activation via suppressing STUB1-mediated IL-4Rα ubiquitination in asthma

Chen,

Huang

et al. 2024

Preprint

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RationaleIL-4 receptor (IL-4R)-mediated alternative activation of macrophage drives type 2 airway inflammation. Cadherin-26 (CDH26) upregulates epithelial type II IL-4R signaling in asthma. However, whether CDH26 contributes to type I IL-4R-mediated macrophage activation and the mechanism by which CDH26 upregulates IL-4R expression remains unknown.ObjectivesTo investigate whether CDH26 promotes macrophage alternative activation via suppressing IL-4Rα ubiquitination-proteasomal degradation.MethodsCDH26 expression in bronchoalveolar lavage cells of asthma patients was examined using quantitative PCR and immunostaining. Airway inflammation and macrophage activation were assessed in ovalbumin-sensitized and challenged macrophage-specificCdh26-deficient mice. Mechanistic experiments included IL-4Rα degradation and ubiquitination assay, CDH26 co-immunoprecipitation and mass spectrometry analysis.Cdh26siRNA encapsulated lipid nanoparticles were used to treat the mouse model.Measurements and ResultsCDH26 expression was enhanced in bronchoalveolar lavage cells from patients with eosinophilic asthma and was localized to lung macrophages. Airway eosinophilia, mucus overproduction and macrophage alternative activation were significantly suppressed in ovalbumin-challenged macrophage-specificCdh26-deficient mice compared to control mice.Cdh26deficiency inhibits IL-4Rα expression and STAT6 phosphorylation in macrophages in vitro. Furthermore, CDH26 knockdown enhances whereas CDH26 overexpression suppresses IL-4Rα ubiquitination and proteasomal degradation. Mechanistically, CDH26 directly interacts with STUB1 and suppresses the binding of STUB1 to IL-4Rα and subsequent ubiquitination-proteasomal degradation.Cdh26siRNA encapsulated lipid nanoparticles markedly alleviate airway inflammation, mucus overproduction and macrophage alternative activation in the mouse model.ConclusionsCDH26 interacts with STUB1 and suppresses STUB1-mediated IL-4Rα ubiquitination-proteasomal degradation, thereby amplifying IL-4R signaling in macrophages in asthma. CDH26 is a potential therapeutic target for asthma.At a glance commentaryScientific knowledge on the subjectIL-4R signaling drives macrophage alternative activation, mucous cell metaplasia, and type 2 airway inflammation in asthma, but the regulatory mechanism underlying IL-4R expression remains unclear.What this study adds to the fieldCDH26 expression is enhanced in lung macrophages from patients with eosinophilic asthma. Macrophage-specificCdh26deficiency suppresses macrophage alternative activation and airway eosinophilia in a mouse model of allergic airway inflammation. CDH26 directly interacts with STUB1 and suppresses STUB1-mediated IL-4Rα ubiquitination-proteasomal degradation, resulting in sustained activation of IL-4R signaling. Lipid nanoparticles encapsulatingCdh26siRNA effectively alleviate airway eosinophilia and mucus overproduction in the mouse model.

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“…TSLP participates in T H 2 differentiation via the induction of OX40L on myeloid DCs, and importantly, OX40L+DCs are elevated in T2 nasal polyps (NPs) [35]. Oncostatin M (OSM), which belongs to IL-6 family, enhances IL-4Rα expression and collaborates with IL-4 to induce TSLP production [36,37]. Collectively, these findings suggest the importance of epithelial cell derived alarmins for both innate and adaptive T2 CRS.…”

Section: Introductionmentioning

confidence: 99%

Endotypic heterogeneity and pathogenesis in chronic rhinosinusitis

Bai,

Tan,

Kato

2023

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of review This review aims to provide updates in realms of endotypic heterogeneity, pathogenesis at the molecular level, potential of biomarkers, and cutting-edge scope of biologics in CRS. Recent findings High-dimensional analyses, such as transcriptomes, and machine learning, have significantly enhanced CRS endotyping, uncovering diverse pathogenetic mechanisms contributing to its heterogeneity. The dynamic process of epithelial remodeling in CRS pathogenesis has gained more clarity and support as exemplified by IL-13 and oncostatin M (OSM) that are shown intricately linked to epithelial barrier dysfunction. Moreover, anti-dsDNA autoantibody, BAFF, periostin, and cystatin SN show promise as potentials biomarkers, offering diagnostic and prognostic value for CRS. Summary The identification of inflammatory molecules involved in endotype specific signaling pathways provides insights into the underlying mechanisms and verifiable biomarkers for diagnosis and prediction of disease severity. More comprehensive clinical studies should be conducted to facilitate biologics from bench to bedside in treating CRS.

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

Cited by 7 publications

References 47 publications

Interaction of eosinophilic and neutrophilic inflammation in patients with chronic rhinosinusitis

Interaction of eosinophilic and neutrophilic inflammation in patients with chronic rhinosinusitis

Cadherin-26 drives macrophage alternative activation via suppressing STUB1-mediated IL-4Rα ubiquitination in asthma

Endotypic heterogeneity and pathogenesis in chronic rhinosinusitis

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