IL-4Rα expression by airway epithelium and smooth muscle accounts for nearly all airway hyperresponsiveness in murine allergic airway disease

McKnight, Christopher; Potter, Crystal; Finkelman, Fred D.

doi:10.1038/s41385-019-0232-7

Cited by 19 publications

(11 citation statements)

References 47 publications

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“…A second limitation of our study is that the underlying molecular mechanisms were not investigated. For example, previous studies have shown that IL-4 and IL-13 signaling are required for the manifestation of AHR in BALB/c mice exposed to HDM ( Johnson et al, 2007 ; McKnight et al, 2020 ). Further studies will be required to determine whether these types of signaling pathways are ultimately shaping the different susceptibility of C57BL/6 and BALB/c mice to develop AHR by differently modulating ASM contractility.…”

Section: Discussionmentioning

confidence: 99%

Smooth Muscle Hypocontractility and Airway Normoresponsiveness in a Mouse Model of Pulmonary Allergic Inflammation

et al. 2021

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The contractility of airway smooth muscle (ASM) is labile. Although this feature can greatly modulate the degree of airway responsiveness in vivo, the extent by which ASM’s contractility is affected by pulmonary allergic inflammation has never been compared between strains of mice exhibiting a different susceptibility to develop airway hyperresponsiveness (AHR). Herein, female C57BL/6 and BALB/c mice were treated intranasally with either saline or house dust mite (HDM) once daily for 10 consecutive days to induce pulmonary allergic inflammation. The doses of HDM were twice greater in the less susceptible C57BL/6 strain. All outcomes, including ASM contractility, were measured 24 h after the last HDM exposure. As expected, while BALB/c mice exposed to HDM became hyperresponsive to a nebulized challenge with methacholine in vivo, C57BL/6 mice remained normoresponsive. The lack of AHR in C57BL/6 mice occurred despite exhibiting more than twice as much inflammation than BALB/c mice in bronchoalveolar lavages, as well as similar degrees of inflammatory cell infiltrates within the lung tissue, goblet cell hyperplasia and thickening of the epithelium. There was no enlargement of ASM caused by HDM exposure in either strain. Unexpectedly, however, excised tracheas derived from C57BL/6 mice exposed to HDM demonstrated a decreased contractility in response to both methacholine and potassium chloride, while tracheas from BALB/c mice remained normocontractile following HDM exposure. These results suggest that the lack of AHR in C57BL/6 mice, at least in an acute model of HDM-induced pulmonary allergic inflammation, is due to an acquired ASM hypocontractility.

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Section: Discussionmentioning

confidence: 99%

Smooth Muscle Hypocontractility and Airway Normoresponsiveness in a Mouse Model of Pulmonary Allergic Inflammation

et al. 2021

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“…Although targeting Th2 cytokines are not particularly novel, there is continued interest in targeting this pathway in selected asthma endotypes. Recent studies suggest that epithelial cell responses to IL-4/IL-13 increases the IL-4Rα-dependent smooth muscle contribution to airway hyper-responsiveness, supporting IL-4Rα-targeted therapy in asthma (168). Activation of estrogen receptor-β signaling has been shown to downregulate airway hyper-responsiveness and airway remodeling (169).…”

Section: Mesenchymal Cells As "Effectors" Of Airway Remodelingmentioning

confidence: 99%

Airway Remodeling in Asthma

et al. 2020

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Asthma is an inflammatory disease of the airways that may result from exposure to allergens or other environmental irritants, resulting in bronchoconstriction, wheezing, and shortness of breath. The structural changes of the airways associated with asthma, broadly referred to as airway remodeling, is a pathological feature of chronic asthma that contributes to the clinical manifestations of the disease. Airway remodeling in asthma constitutes cellular and extracellular matrix changes in the large and small airways, epithelial cell apoptosis, airway smooth muscle cell proliferation, and fibroblast activation. These pathological changes in the airway are orchestrated by crosstalk of different cell types within the airway wall and submucosa. Environmental exposures to dust, chemicals, and cigarette smoke can initiate the cascade of pro-inflammatory responses that trigger airway remodeling through paracrine signaling and mechanostimulatory cues that drive airway remodeling. In this review, we explore three integrated and dynamic processes in airway remodeling: (1) initiation by epithelial cells; (2) amplification by immune cells; and (3) mesenchymal effector functions. Furthermore, we explore the role of inflammaging in the dysregulated and persistent inflammatory response that perpetuates airway remodeling in elderly asthmatics.

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“…IL-13 acts on different cell types to induce airway remodeling, such as airway epithelial cell [5] and broblasts [6]. More importantly, IL-13 also acts on ASMCs via IL-4 receptor α (IL-4Rα) to participate in AHR [7].…”

Section: Introductionmentioning

confidence: 99%

Role of LncRNA H19/miR-93-5p/Orai1 axis in the regulation of human bronchial smooth muscle cell functions and airway remodeling in murine models of asthma

Xiang¹,

Wan²,

Wang³

et al. 2021

Preprint

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Background Type 2 cytokine Interleukin (IL)-13 regulates airway remodeling in asthma by acting on store-operated Ca2+ entry (SOCE) in airway smooth muscle cells. The underlying mechanisms of this regulating effect of IL-13 are not fully understood. Methods Bioinformatic analysis identified interactions of microRNA 93-5p with Orai1, the pore-forming molecule of SOCE, and long non-coding RNA H19 respectively. We investigated the role of H19/miR-93-5p/Orai1 axis in the regulation of proliferation and migration of in vitro cultured human bronchial smooth muscle cells (hBSMCs) induced by IL-13. Functional relevance of H19 in airway inflammation and airway remodeling was investigated in acute and chronic murine models of asthma. Results IL-13 dose-dependently increased the expression of H19 and Orai1 and decreased the expression of miR-93-5p in hBSMCs; H19 siRNA reversed IL-13-induced miR-93-5p and Orai1 expression, and the proliferation and migration of hBSMCs. IL-13-promoted expression of H19 and Orai1 was reduced by miR-93-5p mimic and enhanced by miR-93-5p inhibitor. IL-13-promoted hBSMCs proliferation was enhanced by miR-93-5p inhibitor but not changed by miR-93-5p mimic; whereas IL-13-promoted hBSMCs migration was enhanced by miR-93-5p inhibitor and reduced by miR-93-5p mimic. MiR-93-5p mimic enhanced the inhibiting effect of H19 siRNA on IL-13-induced Orai1 mRNA expression, whereas miR-93-5p inhibitor reversed the inhibiting effects of H19 siRNA on IL-13-induced H19 and Orai1 mRNA and protein expression. The inhibiting effect of H19 siRNA on IL-13-induced hBSMCs proliferation and migration was reversed by miR-93-5p inhibitor but not changed by miR-935p mimic. In the lungs of both asthma mice models, the expression of H19 and Orai1 was higher than in control mice. In acute asthma mice, H19 siRNA reduced Orai1 expression, inflammatory cell infiltration and goblet cell hyperplasia in the lungs, and IL-13 levels in the bronchoalveolar lavage fluid. In chronic asthma mice, H19 siRNA reduced Orai1 expression, inflammatory cell infiltration, goblet cell hyperplasia, collagen deposition and smooth muscle mass in the lungs, as well as IL-13 levels in the BALF. Conclusion IL-13 increases the proliferation and migration of airway smooth muscle cells by acting on H19/miR-93-5p/Orai1 axis, which also regulates airway inflammation and airway remodeling in murine models of asthma.

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IL-4Rα expression by airway epithelium and smooth muscle accounts for nearly all airway hyperresponsiveness in murine allergic airway disease

Cited by 19 publications

References 47 publications

Smooth Muscle Hypocontractility and Airway Normoresponsiveness in a Mouse Model of Pulmonary Allergic Inflammation

Smooth Muscle Hypocontractility and Airway Normoresponsiveness in a Mouse Model of Pulmonary Allergic Inflammation

Airway Remodeling in Asthma

Role of LncRNA H19/miR-93-5p/Orai1 axis in the regulation of human bronchial smooth muscle cell functions and airway remodeling in murine models of asthma

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