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

Kelly-Scumpia KM, Scumpia PO, Delano MJ, Weinstein JS, Cuenca AG, Wynn JL, Moldawer LL - J. Exp. Med. (2010)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department Surgery, University of Florida College of Medicine, Gainesville, FL 32610, USA.

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.

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Type I IFN deficiency worsens CLP but not endotoxicosis survival. (A) SEV129 and IFNAR−/− mice underwent CLP surgery with a 27-gauge needle, and survival was monitored. The figure is the combination of two separate experiments with similar results (n = 24 per group; *, P = 0.0002 using Fisher’s exact test). (B) SEV129 and IFNAR−/− mice were given an i.p. injection of 500 µg E. coli O111:B4 LPS, and survival was monitored for 7 d. The experiment was performed once (n = 12 per group; *, P = 0.0006 using Fisher’s exact test).
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fig1: Type I IFN deficiency worsens CLP but not endotoxicosis survival. (A) SEV129 and IFNAR−/− mice underwent CLP surgery with a 27-gauge needle, and survival was monitored. The figure is the combination of two separate experiments with similar results (n = 24 per group; *, P = 0.0002 using Fisher’s exact test). (B) SEV129 and IFNAR−/− mice were given an i.p. injection of 500 µg E. coli O111:B4 LPS, and survival was monitored for 7 d. The experiment was performed once (n = 12 per group; *, P = 0.0006 using Fisher’s exact test).

Mentions: While investigating whether type I IFN participates in the adaptive immune suppression that occurs during sepsis (Scumpia et al., 2006; Scumpia et al., 2007), we used our low lethality model of CLP that consistently causes 10–20% mortality. To our surprise, we observed that beginning 2–3 d after sepsis induction, IFNAR−/− mice began to die, whereas control SEV129 mice continued to survive. By 7 d after CLP, only 45% of IFNAR−/− mice were alive compared with 95% of the wild-type SEV129 mice (Fig. 1 A).


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

Kelly-Scumpia KM, Scumpia PO, Delano MJ, Weinstein JS, Cuenca AG, Wynn JL, Moldawer LL - J. Exp. Med. (2010)

Type I IFN deficiency worsens CLP but not endotoxicosis survival. (A) SEV129 and IFNAR−/− mice underwent CLP surgery with a 27-gauge needle, and survival was monitored. The figure is the combination of two separate experiments with similar results (n = 24 per group; *, P = 0.0002 using Fisher’s exact test). (B) SEV129 and IFNAR−/− mice were given an i.p. injection of 500 µg E. coli O111:B4 LPS, and survival was monitored for 7 d. The experiment was performed once (n = 12 per group; *, P = 0.0006 using Fisher’s exact test).
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2822595&req=5

fig1: Type I IFN deficiency worsens CLP but not endotoxicosis survival. (A) SEV129 and IFNAR−/− mice underwent CLP surgery with a 27-gauge needle, and survival was monitored. The figure is the combination of two separate experiments with similar results (n = 24 per group; *, P = 0.0002 using Fisher’s exact test). (B) SEV129 and IFNAR−/− mice were given an i.p. injection of 500 µg E. coli O111:B4 LPS, and survival was monitored for 7 d. The experiment was performed once (n = 12 per group; *, P = 0.0006 using Fisher’s exact test).
Mentions: While investigating whether type I IFN participates in the adaptive immune suppression that occurs during sepsis (Scumpia et al., 2006; Scumpia et al., 2007), we used our low lethality model of CLP that consistently causes 10–20% mortality. To our surprise, we observed that beginning 2–3 d after sepsis induction, IFNAR−/− mice began to die, whereas control SEV129 mice continued to survive. By 7 d after CLP, only 45% of IFNAR−/− mice were alive compared with 95% of the wild-type SEV129 mice (Fig. 1 A).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department Surgery, University of Florida College of Medicine, Gainesville, FL 32610, USA.

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.

Show MeSH
Related in: MedlinePlus