title: Type I interferon signaling in hematopoietic cells is required for survival in mouse polymicrobial sepsis by regulating CXCL10.
abstract: 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.
authors.affiliation: Department Surgery, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Kindra M
authors.initials: KM
authors.lastname: Kelly-Scumpia
authors.forename: Philip O
authors.initials: PO
authors.lastname: Scumpia
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Delano
authors.forename: Jason S
authors.initials: JS
authors.lastname: Weinstein
authors.forename: Alex G
authors.initials: AG
authors.lastname: Cuenca
authors.forename: James L
authors.initials: JL
authors.lastname: Wynn
authors.forename: Lyle L
authors.initials: LL
authors.lastname: Moldawer
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D002432:Cecum / Q000473:pathology; D054357:Chemokine CXCL10 / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D006410:Hematopoiesis / Q000276:immunology; D006801:Humans; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000276:immunology; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology / Q000401:mortality / Q000503:physiopathology; D015398:Signal Transduction
chemical_list: D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta