{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Suzuki Y"],"funding":["GlaxoSmithKline Japan Research Grant 2015","HUSM grant-in-aid","Japan Society for the Promotion of Science"],"pagination":["2216-2228"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9397451"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["18(9)"],"pubmed_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 <i>Atg5</i> (autophagy related 5)-deficient mice and epithelial cell-specific <i>atg5<sup>-/-</sup></i> (<i>Scgb1a1/CCSP-atg5<sup>-/-</sup></i>) obesity-induced mice. House dust mite (HDM)-sensitized <i>atg5<sup>-/-</sup></i> obese mice exhibited marked eosinophilic inflammation and airway hyper-reactivity (AHR), compared to wild-type (WT) obese mice. Analyses of <i>atg5<sup>-/-</sup></i> 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 <i>Atg5</i> induced eosinophilic inflammation in <i>Scgb1a1/CCSP-atg5<sup>-/-</sup></i> obese mice, and genetic analyses of epithelial cells from HDM-immunized <i>atg5<sup>-/-</sup></i> obesity-induced mice showed an elevated expression of thymic stromal lymphopoietin (TSLP) and IL33. Notably, HDM-sensitized <i>atg5<sup>-/-</sup></i> 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.<b>Abbreviations:</b> AHR: airway hyper-reactivity; BAL: bronchoalveolar lavage; C<sub>dyn</sub>: dynamic compliance; BM: bone marrow; HDM: house dust mite; HFD: high-fat diet; ILC2s: type 2 innate lymphocyte cells; ROS: reactive oxygen species; R<sub>L</sub>: lung resistance; TSLP: thymic stromal lymphopoietin; TCC: total cell count; WT: wild type."],"journal":["Autophagy"],"pubmed_title":["Involvement of autophagy in exacerbation of eosinophilic airway inflammation in a murine model of obese asthma."],"pmcid":["PMC9397451"],"funding_grant_id":["A-23","15H06253","16K19448","19K17632","42351E1013455"],"pubmed_authors":["Horiguchi R","Furuhashi K","Enomoto N","Fujisawa T","Shibata K","Horiike Y","Naoi H","Inui N","Aono Y","Suda T","Karayama M","Nakamura Y","Suzuki Y","Akiyama N","Hozumi H"],"additional_accession":[]},"is_claimable":false,"name":"Involvement of autophagy in exacerbation of eosinophilic airway inflammation in a murine model of obese asthma.","description":"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 <i>Atg5</i> (autophagy related 5)-deficient mice and epithelial cell-specific <i>atg5<sup>-/-</sup></i> (<i>Scgb1a1/CCSP-atg5<sup>-/-</sup></i>) obesity-induced mice. House dust mite (HDM)-sensitized <i>atg5<sup>-/-</sup></i> obese mice exhibited marked eosinophilic inflammation and airway hyper-reactivity (AHR), compared to wild-type (WT) obese mice. Analyses of <i>atg5<sup>-/-</sup></i> 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 <i>Atg5</i> induced eosinophilic inflammation in <i>Scgb1a1/CCSP-atg5<sup>-/-</sup></i> obese mice, and genetic analyses of epithelial cells from HDM-immunized <i>atg5<sup>-/-</sup></i> obesity-induced mice showed an elevated expression of thymic stromal lymphopoietin (TSLP) and IL33. Notably, HDM-sensitized <i>atg5<sup>-/-</sup></i> 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.<b>Abbreviations:</b> AHR: airway hyper-reactivity; BAL: bronchoalveolar lavage; C<sub>dyn</sub>: dynamic compliance; BM: bone marrow; HDM: house dust mite; HFD: high-fat diet; ILC2s: type 2 innate lymphocyte cells; ROS: reactive oxygen species; R<sub>L</sub>: lung resistance; TSLP: thymic stromal lymphopoietin; TCC: total cell count; WT: wild type.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Sep","modification":"2025-04-25T19:11:35.372Z","creation":"2025-04-06T07:51:23.728Z"},"accession":"S-EPMC9397451","cross_references":{"pubmed":["35098856"],"doi":["10.1080/15548627.2022.2025571"]}}