Targeted inhibition of β-catenin alleviates airway inflammation and remodeling in asthma via modulating the profibrotic and anti-inflammatory actions of transforming growth factor-β1

Abstract

Background and objective TGF-β1 is a key cytokine involved in airway inflammation and airway remodeling in asthma, owing to its anti-inflammatory and profibrotic effects. In our previous study, we found that the knockdown of cytosolic β-catenin mitigated the profibrogenic effect of TGF-β1 without affecting its anti-inflammatory effect. However, the exact role of targeting β-catenin in asthma is not yet fully demonstrated. In the present study, we investigated the effect and mechanism of targeting β-catenin in OVA-challenged asthmatic rats with airway inflammation and remodeling features. Methods We integrated experimental asthma model and asthma related cell model to explore the effect of targeting β-catenin on airway inflammation and remodeling of asthma. Results Blocking β-catenin with ICG001, a small molecule inhibitor of β-catenin/TCF via binding to CBP, attenuated airway inflammation by increasing the level of the anti-inflammatory cytokines IL-10, IL-35, and reducing the level of proinflammation cytokine IL-17. Suppressing β-catenin with ICG001 has an inhibitory effect on airway remodeling via reducing the level of TGF-β1 and the expression of MMP-7 and Snail, upregulating expression of E-cadherin, downregulating expressions of α-SMA and Fn. Inhibiting β-catenin with ICG001 suppressed TGF-β1-induced proliferation and activation of lung fibroblast (CCC-REPF-1) cells, and blocked TGF-β1-induced, blocked TGF-β1 induced EMT of alveolar type II epithelial (RLE-6TN) cells. Conclusions Blockade of β-catenin/TCF not only prevents TGF-β1 induced EMT and profibrogenic effects involved in pathological remodeling of airway, but also alleviates airway inflammation in asthma by balancing proinflammatory and anti-inflammatory cytokine.

Allergen-specific immunotherapy with Alutard SQ improves allergic inflammation in house-dust mites-induced allergic asthma rats through inactivation of the HMGB1/TLR4/NF-κB pathway

“…AIT increases secretoglobin 1A1 expression in cells of the lower airways from patients with allergic asthma to improve airway inflammatory response (34). It also suppresses TGF-β1 in asthma airway epithelial cells, which regulate airway inflammation and remodeling in asthma due to its anti-inflammatory and profibrotic effect (35,36). Similarly, our study showed that Alutard SQ inhibited the HDM-induced TGF-β1 protein secretion, and airway inflammation.…”

A Practical Strategy for Exploring the Pharmacological Mechanism of Chrysophanol Against Obesity Asthma/Childhood Asthma Comorbidity

“…As one of the gelatin enzymes, MMP-9 binds to CD44 to release stored TGF-β1, which may participate in the remodeling of respiratory tract and lung, such as asthmatic airway remodeling. In addition, OVA-sensitized MMP-2, MMP-8, MMP-9 and MMP-12 in the lung tissue of obese mice were imbalanced, accompanied by high degradation, resulting in excessive deposition of type I and Type III collagen in the lung stroma of obese animals (Vieira and de Oliveira et al, 2020;Huo and Tian et al, 2021).…”

Treatment of Gout with TCM Using Turmeric and Corn Silk: A Concise Review Article and Pharmacology Network Analysis

“…e critical target of corn silk, CTNNB1 (β-catenin), is a member of the cyclic catenin family, whose primary role is to regulate adhesion between cells and intercellular substances. In addition, some studies have indicated that activation of the canonical Wnt-1/β-catenin pathway regulates the immune response and induces appropriate T cell responses [32]. YWHAG and YWHAZ belong to the YWHA protein family.…”