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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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CXCL10 improves outcome by decreasing bacteremia in IFNAR−/− mice. (A) SEV129 wild-type mice (n = 10), IFNAR−/− mice (n = 11), or IFNAR−/− mice with 100 ng CXCL10 6 h and on day 3 after CLP (n = 11). Survival was monitored for 7 d. There was a 50% survival advantage in SEV129 wild-type compared with IFNAR−/− mice, and a 54% survival advantage in IFNAR−/− + CXCL10 compared with IFNAR−/− mice. *, P = 0.01 using Fisher’s exact test. Data are from a single experiment with 10 mice in the SEV129 group and 11 mice in the IFNAR−/− and IFNAR−/− + CXCL10 groups. Two independent survival experiments were performed with consistent results. (B) IFNAR−/− mice underwent CLP surgery, and 6 h after surgery mice were injected with PBS or 100 ng of recombinant IP-10. Mice were sacrificed 48 h after CLP, and bacteremia was determined from dilutions of peritoneal lavage fluid obtained aseptically. Each point represents CFUs from one mouse. P < 0.05 using the Student’s t test. Horizontal bars indicate means. The figure represents data from two independent experiments using four mice per group with similar results. (C) SEV129 wild-type and IFNAR−/− mice were injected with 100 ng CXCL10. Peritoneal cells were harvested 18 h later and were examined by flow cytometry for phagocytic neutrophils (Gr1+CD11b+ cells containing FITC+ latex beads). *, P = 0.001 using one-way ANOVA; *, P < 0.05 using the Tukey post hoc analysis. Error bars indicate SD. The figure represents data from three independent experiments using at least four mice per group with similar results.
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fig5: CXCL10 improves outcome by decreasing bacteremia in IFNAR−/− mice. (A) SEV129 wild-type mice (n = 10), IFNAR−/− mice (n = 11), or IFNAR−/− mice with 100 ng CXCL10 6 h and on day 3 after CLP (n = 11). Survival was monitored for 7 d. There was a 50% survival advantage in SEV129 wild-type compared with IFNAR−/− mice, and a 54% survival advantage in IFNAR−/− + CXCL10 compared with IFNAR−/− mice. *, P = 0.01 using Fisher’s exact test. Data are from a single experiment with 10 mice in the SEV129 group and 11 mice in the IFNAR−/− and IFNAR−/− + CXCL10 groups. Two independent survival experiments were performed with consistent results. (B) IFNAR−/− mice underwent CLP surgery, and 6 h after surgery mice were injected with PBS or 100 ng of recombinant IP-10. Mice were sacrificed 48 h after CLP, and bacteremia was determined from dilutions of peritoneal lavage fluid obtained aseptically. Each point represents CFUs from one mouse. P < 0.05 using the Student’s t test. Horizontal bars indicate means. The figure represents data from two independent experiments using four mice per group with similar results. (C) SEV129 wild-type and IFNAR−/− mice were injected with 100 ng CXCL10. Peritoneal cells were harvested 18 h later and were examined by flow cytometry for phagocytic neutrophils (Gr1+CD11b+ cells containing FITC+ latex beads). *, P = 0.001 using one-way ANOVA; *, P < 0.05 using the Tukey post hoc analysis. Error bars indicate SD. The figure represents data from three independent experiments using at least four mice per group with similar results.

Mentions: Indeed, treatment of IFNAR−/− mice with CXCL10 6 and 72 h after CLP improved survival compared with IFNAR−/− mice treated with vehicle control (P = 0.01 using Fisher’s exact test; Fig. 5 A), and brought survival close to wild-type levels (54% in SEV mice vs. 50% in IFNAR−/− mice with CXCL10). Similarly, a single dose of CXCL10 6 h after CLP caused an increase in bacterial peritoneal clearance, resulting in decreased peritoneal bacterial counts 48 h after CLP (P = 0.01 using the Mann-Whitney U test; Fig. 5 B).


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)

CXCL10 improves outcome by decreasing bacteremia in IFNAR−/− mice. (A) SEV129 wild-type mice (n = 10), IFNAR−/− mice (n = 11), or IFNAR−/− mice with 100 ng CXCL10 6 h and on day 3 after CLP (n = 11). Survival was monitored for 7 d. There was a 50% survival advantage in SEV129 wild-type compared with IFNAR−/− mice, and a 54% survival advantage in IFNAR−/− + CXCL10 compared with IFNAR−/− mice. *, P = 0.01 using Fisher’s exact test. Data are from a single experiment with 10 mice in the SEV129 group and 11 mice in the IFNAR−/− and IFNAR−/− + CXCL10 groups. Two independent survival experiments were performed with consistent results. (B) IFNAR−/− mice underwent CLP surgery, and 6 h after surgery mice were injected with PBS or 100 ng of recombinant IP-10. Mice were sacrificed 48 h after CLP, and bacteremia was determined from dilutions of peritoneal lavage fluid obtained aseptically. Each point represents CFUs from one mouse. P < 0.05 using the Student’s t test. Horizontal bars indicate means. The figure represents data from two independent experiments using four mice per group with similar results. (C) SEV129 wild-type and IFNAR−/− mice were injected with 100 ng CXCL10. Peritoneal cells were harvested 18 h later and were examined by flow cytometry for phagocytic neutrophils (Gr1+CD11b+ cells containing FITC+ latex beads). *, P = 0.001 using one-way ANOVA; *, P < 0.05 using the Tukey post hoc analysis. Error bars indicate SD. The figure represents data from three independent experiments using at least four mice per group with similar results.
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Related In: Results  -  Collection

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fig5: CXCL10 improves outcome by decreasing bacteremia in IFNAR−/− mice. (A) SEV129 wild-type mice (n = 10), IFNAR−/− mice (n = 11), or IFNAR−/− mice with 100 ng CXCL10 6 h and on day 3 after CLP (n = 11). Survival was monitored for 7 d. There was a 50% survival advantage in SEV129 wild-type compared with IFNAR−/− mice, and a 54% survival advantage in IFNAR−/− + CXCL10 compared with IFNAR−/− mice. *, P = 0.01 using Fisher’s exact test. Data are from a single experiment with 10 mice in the SEV129 group and 11 mice in the IFNAR−/− and IFNAR−/− + CXCL10 groups. Two independent survival experiments were performed with consistent results. (B) IFNAR−/− mice underwent CLP surgery, and 6 h after surgery mice were injected with PBS or 100 ng of recombinant IP-10. Mice were sacrificed 48 h after CLP, and bacteremia was determined from dilutions of peritoneal lavage fluid obtained aseptically. Each point represents CFUs from one mouse. P < 0.05 using the Student’s t test. Horizontal bars indicate means. The figure represents data from two independent experiments using four mice per group with similar results. (C) SEV129 wild-type and IFNAR−/− mice were injected with 100 ng CXCL10. Peritoneal cells were harvested 18 h later and were examined by flow cytometry for phagocytic neutrophils (Gr1+CD11b+ cells containing FITC+ latex beads). *, P = 0.001 using one-way ANOVA; *, P < 0.05 using the Tukey post hoc analysis. Error bars indicate SD. The figure represents data from three independent experiments using at least four mice per group with similar results.
Mentions: Indeed, treatment of IFNAR−/− mice with CXCL10 6 and 72 h after CLP improved survival compared with IFNAR−/− mice treated with vehicle control (P = 0.01 using Fisher’s exact test; Fig. 5 A), and brought survival close to wild-type levels (54% in SEV mice vs. 50% in IFNAR−/− mice with CXCL10). Similarly, a single dose of CXCL10 6 h after CLP caused an increase in bacterial peritoneal clearance, resulting in decreased peritoneal bacterial counts 48 h after CLP (P = 0.01 using the Mann-Whitney U test; Fig. 5 B).

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