Limits...
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.

Show MeSH

Related in: MedlinePlus

Type I IFN signaling does not play a role in inflammation associated with CLP. (A) SEV129 and IFNAR−/− mice underwent CLP surgery and were sacrificed at 0, 6, and 12 h after surgery. Serum cytokine levels from peripheral blood were determined by MILLIPLEX MAP Mouse Cytokine/Chemokine–Premixed 22 Plex kits. Select cytokines in this figure include TNF, KC, IL-6, IL-1β, and IP-10. Each time point was performed once (n = 3 per group per time point; *, P < 0.05 using the Student’s t test). Error bars indicate SD. (B) SEV129 and IFNAR−/−mice underwent CLP surgery and were sacrificed at 12, 48, and 96 h after surgery. Bacteremia was determined from peritoneal lavage fluid plated on sheep blood agar. Each point represents CFUs from one mouse. The experiment was performed three times (n = 3 per group; P < 0.05 using the Student’s t test). Horizontal bars indicate means.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig2: Type I IFN signaling does not play a role in inflammation associated with CLP. (A) SEV129 and IFNAR−/− mice underwent CLP surgery and were sacrificed at 0, 6, and 12 h after surgery. Serum cytokine levels from peripheral blood were determined by MILLIPLEX MAP Mouse Cytokine/Chemokine–Premixed 22 Plex kits. Select cytokines in this figure include TNF, KC, IL-6, IL-1β, and IP-10. Each time point was performed once (n = 3 per group per time point; *, P < 0.05 using the Student’s t test). Error bars indicate SD. (B) SEV129 and IFNAR−/−mice underwent CLP surgery and were sacrificed at 12, 48, and 96 h after surgery. Bacteremia was determined from peritoneal lavage fluid plated on sheep blood agar. Each point represents CFUs from one mouse. The experiment was performed three times (n = 3 per group; P < 0.05 using the Student’s t test). Horizontal bars indicate means.

Mentions: To investigate whether type I IFN had an effect on systemic cytokine responses in our CLP model, Luminex multiplex analysis was performed on plasma samples over the early course of CLP. Type I IFN signaling did not play a major role in the global cytokine or chemokine response after CLP. Preliminary data shows that plasma levels of most cytokines measured, including TNF-α, IL-6, IL-1β, and IL-10 were comparable between SEV129 and IFNAR−/− mice (data not depicted for IL-10; Fig. 2 A). In fact, IFNAR−/− mice produced significantly higher levels of KC, a chemokine highly induced during bacterial infection, 6 h after CLP than their wild-type counterparts (Fig. 2 A). The only cytokine significantly decreased in IFNAR−/− mice was the IFN-inducible chemokine CXCL10, which was decreased by >60% when compared with wild-type levels (IP-10; Fig. 2 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 signaling does not play a role in inflammation associated with CLP. (A) SEV129 and IFNAR−/− mice underwent CLP surgery and were sacrificed at 0, 6, and 12 h after surgery. Serum cytokine levels from peripheral blood were determined by MILLIPLEX MAP Mouse Cytokine/Chemokine–Premixed 22 Plex kits. Select cytokines in this figure include TNF, KC, IL-6, IL-1β, and IP-10. Each time point was performed once (n = 3 per group per time point; *, P < 0.05 using the Student’s t test). Error bars indicate SD. (B) SEV129 and IFNAR−/−mice underwent CLP surgery and were sacrificed at 12, 48, and 96 h after surgery. Bacteremia was determined from peritoneal lavage fluid plated on sheep blood agar. Each point represents CFUs from one mouse. The experiment was performed three times (n = 3 per group; P < 0.05 using the Student’s t test). Horizontal bars indicate means.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig2: Type I IFN signaling does not play a role in inflammation associated with CLP. (A) SEV129 and IFNAR−/− mice underwent CLP surgery and were sacrificed at 0, 6, and 12 h after surgery. Serum cytokine levels from peripheral blood were determined by MILLIPLEX MAP Mouse Cytokine/Chemokine–Premixed 22 Plex kits. Select cytokines in this figure include TNF, KC, IL-6, IL-1β, and IP-10. Each time point was performed once (n = 3 per group per time point; *, P < 0.05 using the Student’s t test). Error bars indicate SD. (B) SEV129 and IFNAR−/−mice underwent CLP surgery and were sacrificed at 12, 48, and 96 h after surgery. Bacteremia was determined from peritoneal lavage fluid plated on sheep blood agar. Each point represents CFUs from one mouse. The experiment was performed three times (n = 3 per group; P < 0.05 using the Student’s t test). Horizontal bars indicate means.
Mentions: To investigate whether type I IFN had an effect on systemic cytokine responses in our CLP model, Luminex multiplex analysis was performed on plasma samples over the early course of CLP. Type I IFN signaling did not play a major role in the global cytokine or chemokine response after CLP. Preliminary data shows that plasma levels of most cytokines measured, including TNF-α, IL-6, IL-1β, and IL-10 were comparable between SEV129 and IFNAR−/− mice (data not depicted for IL-10; Fig. 2 A). In fact, IFNAR−/− mice produced significantly higher levels of KC, a chemokine highly induced during bacterial infection, 6 h after CLP than their wild-type counterparts (Fig. 2 A). The only cytokine significantly decreased in IFNAR−/− mice was the IFN-inducible chemokine CXCL10, which was decreased by >60% when compared with wild-type levels (IP-10; Fig. 2 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