Unveiling a macrophage-driven inflammatory dysregulation: NF-κB-mediated hyperinflammation links 6PPD-Q exposure to viral immunopathology

Respiratory viral infections contribute substantially to global disease burden and mortality. N -(1,3-dimethylbutyl)- N ′-phenyl- p -phenylenediamine quinone (6PPD-Q) has garnered significant attention due to its marked ecotoxicity. However, it remains unclear how this prevalent environmental pollutant impacts host immune defense against respiratory viral infections. This study established a murine model involving 14-day consecutive intranasal administration of environmentally relevant doses of 6PPD-Q coupled with intranasal instillation of influenza A virus (IAV) or tail vein injection of vesicular stomatitis virus (VSV). Our findings revealed that mice pre-exposed to 6PPD-Q exhibited higher mortality during viral infection. Notably, 6PPD-Q exposure resulted in extensive viral dissemination, severe pulmonary pathology, and markedly dysregulated inflammation, characterized by excessive increases in IL-6, TNF-α, IL-1β, and IL-10. Immune profiling demonstrated that 6PPD-Q exposure induced the selective accumulation of neutrophils, monocytes, and monocyte-derived macrophages (MDMs) in the lungs during IAV infection. Interestingly, macrophage depletion unequivocally abolished the differences of survival, viral loads, and cytokine levels between the vehicle- and 6PPD-Q-treated mice. Mechanistically, 6PPD-Q activated NF-κB signaling in pulmonary MDMs, driving excessive inflammatory responses. Our findings confirm that 6PPD-Q significantly increases host susceptibility to viral pneumonia. This underscores the critical significance of environmental health management in the prevention and control of respiratory infectious diseases.