Adipocyte-Eosinophil Communication and Its Role in Regulation of Airway Function

The concurrent rise in the prevalence of asthma and obesity poses a significant burden on health care system. Obesity accompanied by loss of insulin sensitivity and compensatory hyperinsulinemia drives severe inflammation and is a defining feature of poorly controlled asthma endotype. While we recognize that obesity exacerbates and promotes asthmatic inflammation, the precise immunological and metabolic mechanisms governing interactions between adipose tissue and the airway remain poorly understood. This knowledge gap presents a significant roadblock in the development of effective therapeutic strategies for obese asthma patients. Our recent novel findings show that in lean mice, adipose tissue recruits eosinophils and undergoes adipocyte beiging and lipolysis in response to airway allergic inflammation in models of asthma. This discovery is of paramount importance as it demonstrates, rather surprisingly, that adipose tissue and its resident eosinophils play essential roles in the systemic response to lung allergic reactions. Moreover, we found that in obese mice, adipose eosinophils prevent obesity-induced airway hyperresponsiveness (AHR) by reducing circulating insulin. Collectively, our innovative findings underscore the vital role of communication between adipose tissue and eosinophils in regulating airway function and inflammation in lean and obese mice. However, the phenotype and regulatory nature of eosinophils in fat tissue, and their role in allergic inflammation with and without obesity, remain unresolved. Based on preliminary evidence, we propose the following central hypothesis: adipose eosinophils mobilize in response to airway inflammation and regulate airway function by influencing adipocyte function and systemic energy metabolism. We will test this hypothesis with the following three Specific Aims: (1) To determine adipose tissue and systemic metabolic response to lung inflammation in lean and obese mice; (2) To determine regulatory nature of adipose eosinophil subset and impact of eosinophils on adipocyte responses during airway inflammation in lean and obese mice; (3) To determine the impact of regulatory eosinophils within adipose tissue on obesity-related lung inflammation and airway hyperresponsiveness (AHR). Completion of these aims will elucidate mechanisms underlying bidirectional communication between lung and adipose tissue in obese and non-obese asthma. Furthermore, this research stands as a pivotal milestone in the development of efficacious therapeutic interventions for managing these interrelated comorbid conditions. Project Number: 1R01AI184705-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Sergejs Berdnikovs (+1 co-PI) | Institution: UNIVERSITY OF COLORADO DENVER, Aurora, CO | Award Amount: $730,392 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 IMHA-B (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18470501A1