Glucagon‐like peptide‐1 receptor agonist inhibits aeroallergen‐induced activation of ILC2 and neutrophilic airway inflammation in obese mice

Background Obesity is a risk factor for the development of asthma. However, pharmacologic therapeutic strategies that specifically target obese asthmatics have not been identified. We hypothesize that glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) treatment inhibits aeroallergen‐induced early innate airway inflammation in a mouse model of asthma in the setting of obesity. Methods SWR (lean) and TALLYHO (obese) mice were challenged intranasally with Alternaria alternata extract (Alt‐Ext) or PBS for 4 consecutive days concurrent with GLP‐1RA or vehicle treatment. Results TALLYHO mice had greater Alt‐Ext‐induced airway neutrophilia and lung protein expression of IL‐5, IL‐13, CCL11, CXCL1, and CXCL5, in addition to ICAM‐1 expression on lung epithelial cells compared with SWR mice, and all endpoints were reduced by GLP‐1RA treatment. Alt‐Ext significantly increased BALF IL‐33 in both TALLYHO and SWR mice compared to PBS challenge, but there was no difference in the BALF IL‐33 levels between these two strains. However, TALLYHO, but not SWR, mice had significantly higher airway TSLP in BALF following Alt‐Ext challenge compared to PBS, and BALF TSLP was significantly greater in TALLYHO mice compared to SWR mice following airway Alt‐Ext challenge. GLP‐1RA treatment significantly decreased the Alt‐Ext‐induced TSLP and IL‐33 release in TALLYHO mice. While TSLP or ST2 inhibition with a neutralizing antibody decreased airway eosinophils, they did not reduce airway neutrophils in TALLYHO mice. Conclusions These results suggest that GLP‐1RA treatment may be a novel pharmacologic therapeutic strategy for obese persons with asthma by inhibiting aeroallergen‐induced neutrophilia, a feature not seen with either TSLP or ST2 inhibition. Polygenic obese mice have larger level of Altrernaria extract‐induced TSLP, the number of lung ILC2, neutrophils in the airway, and ICAM‐1 on lung epithelial cells compared with lean mice. GLP‐1RA decreases the Altrernaria extract‐induced IL‐33 and TSLP release, type‐2 inflammation mediated by ILC2, eosinophilia and neutrophilia in the airway, and airway responsiveness in polygenic obese mice. Our findings indicate the potential for a new pharmacological therapeutic strategy to patients with asthma in the setting of obesity. Abbreviations: ICAM‐1, intercellular adhesion molecule 1; ILC2, group 2 innate lymphoid cells; GLP‐1RA, glucagon‐like peptide‐1 agonist