Galectin-3 exacerbates influenza a virus pathogenesis via dual mechanisms: Promoting hemagglutinin-dependent entry and driving nlrp3 inflammasome activation.
Influenza A viruses (IAVs), particularly highly pathogenic avian influenza (HPAI) strains like H5N1 and H7N9, cause severe pneumonia and acute respiratory distress syndrome (ARDS) driven by dysregulated cytokine storms. A key mediator of this immunopathology is the excessive activation of the NLRP3 inflammasome, which governs the maturation of IL-1β. Galectin-3 (Gal3), a β-galactoside-binding lectin, is upregulated during infection; however, its specific regulatory role in coordinating NLRP3 inflammasome activation across distinct viral hemagglutinin (HA) subtypes remains to be elucidated. In this study, we demonstrate that Gal3 functions as a critical amplifier of influenza pathogenesis through a distinct dual-stage mechanism. Results from viral binding and internalization assays indicate that extracellular Gal3 promotes viral entry by interacting with viral HA, an effect that is strictly strain-dependent (H5N1 > H1N1 > H7N9). This enhanced entry consequently amplifies the initial signal for inflammasome activation. Intracellularly, Gal3 regulates the NLRP3 cascade by sustaining NF-κB activation (priming) to upregulate NLRP3 and pro-IL-1β transcription and acting as a facilitator to strengthen the NLRP3-ASC-pro-caspase-1 interaction, promoting ASC oligomerization (activation). Consistently, in vivo studies demonstrate that Gal3-deficient mice exhibit significantly improved survival, reduced weight loss, and attenuated pulmonary inflammation and IL-1β release following infection, with the most pronounced protective effects observed against H5N1. Collectively, these findings identify Gal3 as a potent host factor that orchestrates excessive inflammation by simultaneously facilitating viral entry and driving the assembly of the NLRP3 inflammasome, highlighting the Gal3-NLRP3 axis as a promising therapeutic target to mitigate severe influenza-induced lung injury.