The Role of β-Catenin in Lung ILC-2 Functions

Influenza A virus (IAV) disproportionally affects adults aged ≥ 65, resulting in significant morbidity and mortality due to impaired type-2 immune responses mediated by innate lymphoid cells group- 2 (ILC-2). Our data revealed a critical role of β-catenin in modulating ILC-2 function, which declines with age. Using innovative mouse models, we demonstrated that β-catenin stabilization enhances ILC-2 survival and function, leading to improved resistance against IAV infection. Our study utilizes both loss-of-function (LOF) and gain-of-function (GOF) mouse models to detail the effects of β-catenin levels on ILC-2 numbers and their effector functions, specifically GATA3 and T-bet expression. Results indicate that β-catenin stabilization in GOF models results in significant increases in ILC-2 counts, enhanced Th1 effector immunity, and reduced lung damage upon IAV challenge, whereas LOF models show detrimental outcomes. The proposed proposal aims to elucidate the mechanisms by which β-catenin influences ILC-2 dynamics and its interaction with key transcriptional regulators such as GATA3 and TCF-1, potentially through the canonical Wnt signaling pathway. We will examine the effects of a novel β-catenin-stabilizing small molecule, A124, on ILC-2 populations in mouse and human lung tissues. This will include examining β-catenin's role in modulating immune responses without causing systemic toxicity. Our multidisciplinary team combines expertise in ILC-2 biology, β-catenin signaling, and clinical insights from thoracic surgery and pulmonology to translate these findings into potential therapeutic strategies for enhancing immune protection in the elderly. This research is pivotal for developing targeted interventions against IAV and possibly other respiratory pathogens in vulnerable populations. Project Number: 1R21AG098389-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: MOBIN KARIMI | Institution: UPSTATE MEDICAL UNIVERSITY, SYRACUSE, NY | Award Amount: $461,138 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 RCCS-Y (03)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11288675