Type I interferon signaling in hematopoietic cells is required for survival in mouse polymicrobial sepsis by regulating CXCL10

• Published in: The Journal of experimental medicine Vol. 207; no. 2; pp. 319 - 326
• Main Authors: Kelly-Scumpia, Kindra M, Scumpia, Philip O, Delano, Matthew J, Weinstein, Jason S, Cuenca, Alex G, Wynn, James L, Moldawer, Lyle L
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 15.02.2010
• Subjects: Adaptive Immunity; Animals; Brief Definitive Report; Cecum - pathology; Chemokine CXCL10 - immunology; Chemokine CXCL10 - metabolism; Disease Models, Animal; Hematopoiesis - immunology; Humans; Interferon Type I - immunology; Interferon Type I - metabolism; Mice; Neutrophil Infiltration - immunology; Neutrophils - immunology; Phagocytosis - immunology; Receptor, Interferon alpha-beta - deficiency; Receptor, Interferon alpha-beta - immunology; Sepsis - immunology; Sepsis - microbiology; Sepsis - mortality; Sepsis - physiopathology; Signal Transduction
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20091959

Type I interferon (IFN) alpha/beta is critical for host defense. During endotoxicosis or highly lethal bacterial infections where systemic inflammation predominates, mice deficient in IFN-alpha/beta receptor (IFNAR) display decreased systemic inflammation and improved outcome. However, human sepsis mortality often occurs during a prolonged period of immunosuppression and not from exaggerated inflammation. We used a low lethality cecal ligation and puncture (CLP) model of sepsis to determine the role of type I IFNs in host defense during sepsis. Despite increased endotoxin resistance, IFNAR(-/-) and chimeric mice lacking IFNAR in hematopoietic cells display increased mortality to CLP. This was not associated with an altered early systemic inflammatory response, except for decreased CXCL10 production. IFNAR(-/-) mice display persistently elevated peritoneal bacterial counts compared with wild-type mice, reduced peritoneal neutrophil recruitment, and recruitment of neutrophils with poor phagocytic function despite normal to enhanced adaptive immune function during sepsis. Importantly, CXCL10 treatment of IFNAR(-/-) mice improves survival and decreases peritoneal bacterial loads, and CXCL10 increases mouse and human neutrophil phagocytosis. Using a low lethality sepsis model, we identify a critical role of type I IFN-dependent CXCL10 in host defense during polymicrobial sepsis by increasing neutrophil recruitment and function.