STAT6 Blockade Abrogates Aspergillus-Induced Eosinophilic Chronic Rhinosinusitis and Asthma, A Model of Unified Airway Disease

Sun, Hua; Damania, Ashish; Mair, Megan; Otukoya, Eniola; Li, Yidong; Polsky, Katherine; Zeng, Yuying; Alt, Jeremiah A.; Citardi, Martin J.; Corry, David B.; Luong, Amber U.; Knight, John

doi:10.3389/fimmu.2022.818017

Cited by 5 publications

(3 citation statements)

References 64 publications

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“…Thus, it is possible that STAT6, but not STAT1 and STAT3, might be a crucial signal transducer in the development of ECRS. STAT6 is essential for ECRS, as demonstrated by Sun et al 39 In this article, the authors focused on the functions of STAT6 rather than other STAT family members in ECRS. Another study using JAK inhibitor-treated eosinophilic CRSwNP in a mouse model indicated that by inhibiting STAT6 phosphorylation, the Th2 response and eosinophilic inflammation can be reduced.…”

Section: Discussionmentioning

confidence: 98%

Activation of STAT6 by intranasal allergens correlated with the development of eosinophilic chronic rhinosinusitis in a mouse model

Wei

Sun

et al. 2022

Int J Immunopathol Pharmacol

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Eosinophilic chronic rhinosinusitis (ECRS) is a chronic inflammatory disease characterized by prominent eosinophilic infiltration along with a T-helper-2 (Th2) response. It has been well documented that signal transducer and activator of transcription 6 (STAT6) is a nuclear transcription factor that mediates Th2-type immunity and is implicatory of STAT1 and STAT3 in the pathogenesis of allergic airway diseases. However, little is known about the association between STATs and ECRS. Here, we explored the relationship between STAT1, STAT3, and/or STAT6 and eosinophilic inflammation accompanied by Th2-type immunity in a mouse model of ECRS. An ovalbumin (OVA)-staphylococcal enterotoxin B (SEB)-induced ECRS murine model was first established. The mucosal histological alterations were determined using hematoxylin and eosin staining. The number of eosinophils in peripheral blood was measured using a blood cell analyzer. The cytokine (IL-4, IL-5, IL17 A and IFN-γ) expression levels in the sinonasal mucosa and total and OVA-specific IgE from serum were measured using ELISA. Then, the protein levels of STAT1, STAT3, STAT6, phosphorylated STAT1 (p-STAT1), p-STAT3, p-STAT6, T-box expressed in T-cells (T-bet), GATA binding protein 3 (GATA-3), and retinoic acid receptor-related orphan receptor γ (RORγt) in the sinonasal mucosa were examined by immunohistochemical staining or Western blotting. Local administration of OVA combined with SEB (OVA + SEB) induced multiple polyp-like lesions, accompanied by prominent eosinophilic infiltration in the sinonasal mucosa. The OVA- and OVA+SEB-treated groups showed significantly higher eosinophil counts from peripheral blood and total and OVA-specific IgE levels from serum than those in the PBS- and SEB-treated groups. The levels of p-STAT6 were markedly increased by OVA + SEB exposure, as well as GATA-3, IL-4, and IL-5, but did not affect STAT6, p-STAT1, p-STAT3, T-bet, RORγt, IFN-γ, or IL-17A. Furthermore, an eosinophil count in the sinonasal mucosa showed a positive correlation with the level of p-STAT6 in the ECRS mouse model. Signal transducer and activator of transcription 6 signaling could be activated in the OVA+SEB-induced ECRS model and might be a crucial signal transducer in the development of Th2-skewed ECRS.

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Section: Discussionmentioning

confidence: 98%

Activation of STAT6 by intranasal allergens correlated with the development of eosinophilic chronic rhinosinusitis in a mouse model

Wei

Sun

et al. 2022

Int J Immunopathol Pharmacol

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“…This pathway is involved in the polarization of T helper cells and colony-stimulating factors [163,164] and could potentially be a target for future therapeutic options in CRS. It has been documented that phosphorylated STAT6 but not STAT1 and STAT3 are significantly increased in the sinonasal mucosa after allergen stimulation in a murine model of chronic eosinophilic airway inflammation [165,166], and STAT6 gene silencing ameliorated allergic rhinitis [167] and inhibited allergic airways inflammation [168,169]. In an interventional study of mice, topical tofacitinib administration was shown to be an effective treatment for eosinophilic CRSwNP by inhibiting phosphorylation, especially of STAT6, and decreasing the levels of eosinophil cationic protein and eotaxins [170].…”

Section: Targeting Janus Kinasesmentioning

confidence: 99%

Targeting Epithelium Dysfunction and Impaired Nasal Biofilms to Treat Immunological, Functional, and Structural Abnormalities of Chronic Rhinosinusitis

Petalas

Goudakos

Konstantinou

2023

IJMS

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Chronic rhinosinusitis (CRS) with (CRSwNP) or without (CRSsNP) nasal polyps is a prevalent and heterogeneous disorder existing as a spectrum of clinical conditions with complex underlying pathomechanisms. CRS comprises a broad syndrome characterized by multiple immunological features involving complex interactions between the genes, the microbiome, host- and microbiota-derived exosomes, the epithelial barrier, and environmental and micromilieu exposures. The main pathophysiological feature is an epithelial barrier disruption, accompanied by microbiome alterations and unpredictable and multifactorial immunologic overreactions. Extrinsic pathogens and irritants interact with multiple epithelial receptors, which show distinct expression patterns, activate numerous signaling pathways, and lead to diverse antipathogen responses. CRSsNP is mainly characterized by fibrosis and mild inflammation and is often associated with Th1 or Th17 immunological profiles. CRSwNP appears to be associated with moderate or severe type 2 (T2) or Th2 eosinophilic inflammation. The diagnosis is based on clinical, endoscopic, and imaging findings. Possible CRS biomarkers from the peripheral blood, nasal secretions, tissue biopsies, and nasally exhaled air are studied to subgroup different CRS endotypes. The primary goal of CRS management is to maintain clinical control by nasal douching with isotonic or hypertonic saline solutions, administration of nasal and systemic steroids, antibiotics, biologic agents, or, in persistent and more severe cases, appropriate surgical procedures.

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“…However, when inhibiting STAT6, IL-4 or IL-13 exhibited to reduce FABP4 expression, suggesting that the role of FABP4 is regulated by its binding to STAT6, implying the important role of STAT6 in asthma inflammation [139,140]. By interfering with the interaction of STAT-6-MAP kinase with ERK1/2 and p38, or suppressing STAT-6 serine phosphorylation, STAT-6 can be inhibited from activation and acetylation [141][142][143]. Serine kinases are essential in phosphorylating serine residues in STAT-6 to promote its transactivation, therefore, inhibitors of these kinases related to FA and amino acid metabolism may be potential targets in asthma treatment.…”

Section: Targets In Il-4/il-13/janus Kinase/stat-6 Pathwaymentioning

confidence: 99%

Immunometabolism in the pathogenesis of asthma

Qin,

Chen,

Wang

et al. 2023

Immunology

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Bronchial asthma is a heterogeneous disease characterised by chronic airway inflammation. A variety of immune cells such as eosinophils, mast cells, T lymphocytes, neutrophils and airway epithelial cells are involved in the airway inflammation and airway hyperresponsiveness in asthma pathogenesis, resulting in extensive and variable reversible expiratory airflow limitation. However, the precise molecular mechanisms underlying the allergic immune responses, particularly immunometabolism, remains unclear. Studies have detected enhanced oxidative stress, and abnormal metabolic progresses of glycolysis, fatty acid and amino acid in various immune cells, inducing dysregulation of innate and adaptive immune responses in asthma pathogenesis. Immunometabolism mechanisms contain multiple signalling pathways, providing novel therapy targets for asthma. This review summarises the current knowledge on immunometabolism reprogramming in asthma pathogenesis, as well as potential therapy strategies.

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STAT6 Blockade Abrogates Aspergillus-Induced Eosinophilic Chronic Rhinosinusitis and Asthma, A Model of Unified Airway Disease

Cited by 5 publications

References 64 publications

Activation of STAT6 by intranasal allergens correlated with the development of eosinophilic chronic rhinosinusitis in a mouse model

Activation of STAT6 by intranasal allergens correlated with the development of eosinophilic chronic rhinosinusitis in a mouse model

Targeting Epithelium Dysfunction and Impaired Nasal Biofilms to Treat Immunological, Functional, and Structural Abnormalities of Chronic Rhinosinusitis

Immunometabolism in the pathogenesis of asthma

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