Fyn deficiency drives pro-inflammatory macrophage activation to exacerbate septic acute lung injury

Macrophage-driven inflammation is a hallmark of sepsis-associated acute lung injury (ALI). Fyn, a Src family kinase, plays a pivotal role in diverse cellular signaling pathways. While prior studies established that Toll-like receptor (TLR) activation rapidly initiates Fyn activation, its precise immunoregulatory functions and role in sepsis-induced ALI remain contentious. In this study, we investigated the impact of Fyn deficiency on cecal ligation and puncture (CLP)-induced septic ALI. Furthermore, we utilized murine bone marrow-derived macrophages (BMDMs) and human THP-1-derived macrophages to elucidate the influence of Fyn on macrophage inflammatory responses. Fyn deficiency significantly exacerbated pulmonary inflammation and injury in ALI mice, as evidenced by histopathological analysis of lung tissue, elevated cytokine levels, and reduced survival. Notably, Fyn deficiency potentiated macrophage inflammatory responses. This effect was mediated through the suppression of TNF receptor-associated factor 6 (TRAF6) ubiquitination and degradation, thereby augmenting TLR4-NF-κB signaling. Consequently, Fyn deficiency led to excessive macrophage cytokine production and exacerbated ALI severity. Collectively, these findings underscore Fyn as a critical immunomodulator and highlight its potential as a therapeutic target for immunomodulation and anti-inflammatory strategies in sepsis-induced ALI and related acute inflammatory disorders.