Abstract
Respiratory viruses, including the influenza virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), pose significant health threats. As tissue-resident macrophages, alveolar macrophages (AM) are crucial for defending against respiratory viral infection by producing cytokines, engulfing virus-infected cells, and promoting wound healing. However, excessive inflammatory responses can lead to tissue injury. Growing evidence indicates that astragaloside IV (AST IV) regulates innate immune responses. Specifically, AST IV balances the inflammatory response to mitigate tissue damage and promote tissue repair. However, whether AST IV directly targets AM to alleviate lung damage induced by respiratory viral infection remains unclear. Our results demonstrate that AST IV treatment significantly reduces morbidity and mortality in mice during IAV infection. AST IV markedly decreases proinflammatory cytokine levels, mitigates lung injury and promotes lung recovery through enhancing the repair capacity mediated by alveolar type II cells. Mechanistically, AST IV suppresses the Wnt/β-catenin signalling pathway, which is critical for driving inflammatory responses in AM while maintaining mitochondrial fitness. Thus, our findings suggest that AST IV effectively targets AM to alleviate inflammation and lung damage caused by respiratory viral infections, highlighting its potential as a therapeutic agent for managing viral pneumonia.