Critical Role of SerpinB1 in Regulating Inflammatory Responses in Pulmonary Influenza Infection

• Published in: The Journal of infectious diseases Vol. 204; no. 4; pp. 592 - 600
• Main Authors: Gong, Dapeng, Farley, Kalamo, White, Mitchell, Hartshorn, Kevan L., Benarafa, Charaf, Remold-O'Donnell, Eileen
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.08.2011
• Subjects: Animals; Biological and medical sciences; Cell Death; Cytokines; Cytokines - genetics; Cytokines - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - physiology; Infections; Infectious diseases; Inflammation - metabolism; Inflammation - pathology; Influenza A Virus, H3N2 Subtype; Lung - pathology; Lung Diseases - pathology; Lung Diseases - virology; Lungs; Macrophages; Major and Brief Reports; Medical sciences; Mice; Mice, Knockout; Microbiology; Monocytes; Neutrophils; Orthomyxoviridae; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - pathology; Serpins - genetics; Serpins - metabolism; T lymphocytes; Time Factors; Viruses; USA, Pennsylvania, Philadelphia; Infection; Inflammation; Viral disease; Influenza
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jir352

Background. Excessive inflammatory host response increases morbidity and mortality associated with seasonal respiratory influenza, and highly pathogenic virus strains are characterized by massive infiltration of monocytes and/or macrophages that produce a storm of injurious cytokines. Methods. Here, we examined the role in respiratory influenza of serpinB1, an endogenous inhibitor of the serine proteases elastase, cathepsin G, and proteinase-3, increasingly recognized as regulators of inflammation. Results. After challenge with high-dose surfactant protein-D (SP-D)-sensitive influenza A/Philadelphia/82 (H3N2), serpinB1 –/– mice died earlier and in greater numbers than did wild-type mice. Sublethally infected animals suffered increased morbidity, delayed resolution of epithelial injury, and increased immune cell death. Viral clearance and SP-D/SP-A upregulation were unimpaired and so were early virus-induced cytokine and chemokine burst and influx of large numbers of neutrophils and monocytes. Whereas initial cytokines and chemokines rapidly cleared in wild-type mice, TNF-α, IL-6, KC/CXCL1, G-CSF, IL-17A, and MCP-1/CCL2 remained elevated in serpinB1 –/– mice. Monocyte-derived cells were the dominant immune cells in influenza-infected lungs, and those from serpinB1 –/– mice produced excessive IL-6 and TNF-a when tested ex vivo. Pulmonary γδ T-cells that produced IL-17A were also increased. Conclusions. Because viral clearance was unimpaired, the study highlights the critical role of serpinB1 in mitigating inflammation and restricting pro-inflammatory cytokine production in influenza infection.