Involvement of autophagy in exacerbation of eosinophilic airway inflammation in a murine model of obese asthma

Abstract

Obesity is a common comorbidity in patients with asthma, and obese asthma patients present the most refractory phenotype among patients with severe asthma. Similar to the observations in non-obese asthma patients, clinical studies have revealed heterogeneity in obese asthma patients, including the occurrences of T helper (Th)2-high and Th2-low phenotypes. However, the mechanisms underlying obesity-related asthma are not completely understood. Though macroautophagy/autophagy is involved in asthma and obesity, its role in obesity-associated asthma is unknown. We hypothesized that autophagy is involved in the pathogenesis of obese asthma. For our investigations, we used high-fat diet-induced Atg5 (autophagy related 5)-deficient mice and epithelial cell-specific atg5 −/− ( Scgb1a1/CCSP-atg5 −/− ) obesity-induced mice. House dust mite (HDM)-sensitized atg5 −/− obese mice exhibited marked eosinophilic inflammation and airway hyper-reactivity (AHR), compared to wild-type (WT) obese mice. Analyses of atg5 −/− obese mice showed increased levels of Th2 cells but not ILC2s together with elevated expression of Th2 cytokines in the lung. In response to the HDM challenge, activated epithelial autophagy was observed in lean but not obese WT mice. Epithelium-specific deletion of Atg5 induced eosinophilic inflammation in Scgb1a1/CCSP-atg5 −/− obese mice, and genetic analyses of epithelial cells from HDM-immunized atg5 −/− obesity-induced mice showed an elevated expression of thymic stromal lymphopoietin (TSLP) and IL33. Notably, HDM-sensitized atg5 −/− mice developed TSLP- and IL33-dependent eosinophilic inflammation and AHR. Our results suggest that autophagy contributes to the exacerbation of eosinophilic inflammation in obese asthma. Modulations of autophagy may be a therapeutic target in obesity-associated asthma. Abbreviations: AHR: airway hyper-reactivity; BAL: bronchoalveolar lavage; C dyn : dynamic compliance; BM: bone marrow; HDM: house dust mite; HFD: high-fat diet; ILC2s: type 2 innate lymphocyte cells; ROS: reactive oxygen species; R L : lung resistance; TSLP: thymic stromal lymphopoietin; TCC: total cell count; WT: wild type.

Multiomic landscape of immune pathogenesis in Kimura’s disease

“…Previous studies have shown that it contributes to the extracellular trap formation and exacerbation of eosinophilic inflammation in asthma. 29 , 30 , 31 , 32 Heightened ER stress is associated with severe eosinophilic in asthma and lipid mediators such as LTB4, LTD4 and platelet-activating factors are potent chemoattractants for eosinophils. 33 , 34 Of interest, ROS acts as an upstream regulator of ER stress and lipid metabolism.…”

Inadequate therapeutic responses to glucocorticoid treatment in bronchial asthma

“…A recent study suggested that autophagy contributes to the exacerbation of eosinophilic inflammation in obese asthma by the development of TSLP-and IL33dependent eosinophilic inflammation. 71 Mouse studies suggested that the nucleotidebinding domain, leucine-rich repeat-containing family, and pyrin domain-containing-3-IL1b-IL17 axis elicit the relationship between excess adiposity and non-atopic adult-onset asthma. 72,73 Obesity is associated with poorer BA control.…”

The Role of Macrophage Autophagy in Asthma: A Novel Therapeutic Strategy

“…Besides, in ATG5-deficient mice, lack of autophagy causes neutrophilic airway inflammation and hyperreactivity, concomitant with increased IL-1 β and IL-17 levels in lung lysates upon house dust mite sensitization and challenge [ 33 ]. Likewise, enhanced eosinophilic inflammation and airway hyperreactivity are also observed in ATG5-deficient obese mice compared to wild type obese mice, suggesting that autophagy mitigates the exacerbation of eosinophilic inflammation in obese asthma [ 34 ]. Intriguingly, the level of autophagy differs in distinct cell types in asthma-like animal models.…”