B75-30 Macrophage-derived Il-1β Activates IL1R1HighFibroblasts To Secrete CXCL1, Recruiting Pathological CXCR2+Neutrophils And Exacerbating Early Lung Injury In Severe Influenza

Abstract

Neutrophils play a crucial role in severe influenza-induced lung injury. While prior studies have provided insights into neutrophil recruitment into the lungs during severe influenza, the essential mechanisms underlying this process remain incompletely understood. Through a systematic study of a mouse model of severe influenza, we demonstrated that influenza virus drives pathological neutrophil recruitment in the lungs, primarily through an IL-1β-CXCL1 axis during the early stage. Singlecell RNA sequencing identified IFNinduced M1 macrophages as the dominant source of IL-1β, displaying high transcriptional signatures associated with both necroptosis and pyroptosis. In vivo, IL-1β-mediated neutrophil recruitment depended on MLKLmediated necroptosis but not on GSDMD-mediated pyroptosis. Furthermore, CXCR2high neutrophil recruitment mediated by IL-1β is predominantly through fibroblastderived CXCL1. Mechanistically, macrophage-derived IL-1β activated IL-1R1high adventitial fibroblasts, leading to robust CXCL1 production through an NFKBIZdependent pathway. Therapeutic intervention with neutrophildepleting antibodies, CXCL-1neutralizing antibodies, or the CXCR2 antagonist Reparixin during the early stage of infection significantly improved severe influenzainduced lung injury in mice. Collectively, our study delineates a critical IL-1β-CXCL1 axis coordinated by macrophage-fibroblast crosstalk that orchestrates pathogenic neutrophil recruitment. These findings reveal a previously unrecognized virus-host interaction and intercellular network governing neutrophildriven pathology in severe influenza.

This abstract is funded by: National Science Foundation for Young Scientists