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Persistently active microbial molecules prolong innate immune tolerance in vivo.

Lu M, Varley AW, Munford RS - PLoS Pathog. (2013)

Bottom Line: Mice that are unable to inactivate LPS, in contrast, remain tolerant for several months; during this time they respond sluggishly to Gram-negative bacterial challenge, with high mortality.We show here that prolonged macrophage reprogramming is maintained in vivo by the persistence of stimulatory LPS molecules within the cells' in vivo environment, where naïve cells can acquire LPS via cell-cell contact or from the extracellular fluid.Measures that disable microbial molecules might enhance resolution of tissue inflammation and help restore innate defenses in individuals recovering from many different infectious diseases.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America. Lum3@niaid.nih.gov

ABSTRACT
Measures that bolster the resolution phase of infectious diseases may offer new opportunities for improving outcome. Here we show that inactivation of microbial lipopolysaccharides (LPS) can be required for animals to recover from the innate immune tolerance that follows exposure to Gram-negative bacteria. When wildtype mice are exposed to small parenteral doses of LPS or Gram-negative bacteria, their macrophages become reprogrammed (tolerant) for a few days before they resume normal function. Mice that are unable to inactivate LPS, in contrast, remain tolerant for several months; during this time they respond sluggishly to Gram-negative bacterial challenge, with high mortality. We show here that prolonged macrophage reprogramming is maintained in vivo by the persistence of stimulatory LPS molecules within the cells' in vivo environment, where naïve cells can acquire LPS via cell-cell contact or from the extracellular fluid. The findings provide strong evidence that inactivation of a stimulatory microbial molecule can be required for animals to regain immune homeostasis following parenteral exposure to bacteria. Measures that disable microbial molecules might enhance resolution of tissue inflammation and help restore innate defenses in individuals recovering from many different infectious diseases.

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Related in: MedlinePlus

rhAOAH prevents prolonged endotoxin tolerance in vivo.Aoah−/− mice were injected with 1 µg LPS i.p. on day 0. From days 1 to 13, mice were given daily i.p. doses of 0.3 µg rhAOAH or placebo (carrier protein BSA in PBS) (diagonal marking red bars). Peritoneal cells were explanted on day 14 and the adherent macrophages were challenged ex vivo with LPS for 6 hrs before medium cytokine levels were measured. (A), IL-6; (B), TNF; (C), RANTES. Naïve Aoah−/− peritoneal macrophages were used as controls (solid red bars). **, P<0.01; ***, P<0.001. rhAOAH largely prevented prolonged tolerance in vivo.
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ppat-1003339-g009: rhAOAH prevents prolonged endotoxin tolerance in vivo.Aoah−/− mice were injected with 1 µg LPS i.p. on day 0. From days 1 to 13, mice were given daily i.p. doses of 0.3 µg rhAOAH or placebo (carrier protein BSA in PBS) (diagonal marking red bars). Peritoneal cells were explanted on day 14 and the adherent macrophages were challenged ex vivo with LPS for 6 hrs before medium cytokine levels were measured. (A), IL-6; (B), TNF; (C), RANTES. Naïve Aoah−/− peritoneal macrophages were used as controls (solid red bars). **, P<0.01; ***, P<0.001. rhAOAH largely prevented prolonged tolerance in vivo.

Mentions: To test whether providing AOAH to mice can prevent or reverse prolonged tolerance in vivo, we gave Aoah−/− mice LPS i.p. on day 0, followed by rhAOAH or carrier protein BSA i.p. daily from day 1 to day 13. Peritoneal cells were harvested on day 14, plated, and adherent macrophages were rechallenged ex vivo with LPS. LPS-stimulated RANTES and IL-6 were at naïve Aoah−/− macrophage levels in macrophages from animals that had received rhAOAH treatment (Fig. 9A–C). TNF production is the most sensitively reprogrammed component of tolerance in these cells; here the TNF level in culture medium overlying macrophages from LPS-exposed rAOAH-treated mice was significantly lower than the naïve macrophage level but 10-fold higher than the levels produced by macrophages from mice that received carrier protein BSA instead of rhAOAH. Recombinant AOAH was thus able to ameliorate prolonged tolerance in vivo in Aoah−/− animals. Treatment with IFN-γ or antibody to IL-10 receptor did not rescue Aoah−/− animals from prolonged endotoxin tolerance (data not shown), in line with the conclusion that bioactive LPS plays a dominant role in maintaining prolonged tolerance in vivo.


Persistently active microbial molecules prolong innate immune tolerance in vivo.

Lu M, Varley AW, Munford RS - PLoS Pathog. (2013)

rhAOAH prevents prolonged endotoxin tolerance in vivo.Aoah−/− mice were injected with 1 µg LPS i.p. on day 0. From days 1 to 13, mice were given daily i.p. doses of 0.3 µg rhAOAH or placebo (carrier protein BSA in PBS) (diagonal marking red bars). Peritoneal cells were explanted on day 14 and the adherent macrophages were challenged ex vivo with LPS for 6 hrs before medium cytokine levels were measured. (A), IL-6; (B), TNF; (C), RANTES. Naïve Aoah−/− peritoneal macrophages were used as controls (solid red bars). **, P<0.01; ***, P<0.001. rhAOAH largely prevented prolonged tolerance in vivo.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3649966&req=5

ppat-1003339-g009: rhAOAH prevents prolonged endotoxin tolerance in vivo.Aoah−/− mice were injected with 1 µg LPS i.p. on day 0. From days 1 to 13, mice were given daily i.p. doses of 0.3 µg rhAOAH or placebo (carrier protein BSA in PBS) (diagonal marking red bars). Peritoneal cells were explanted on day 14 and the adherent macrophages were challenged ex vivo with LPS for 6 hrs before medium cytokine levels were measured. (A), IL-6; (B), TNF; (C), RANTES. Naïve Aoah−/− peritoneal macrophages were used as controls (solid red bars). **, P<0.01; ***, P<0.001. rhAOAH largely prevented prolonged tolerance in vivo.
Mentions: To test whether providing AOAH to mice can prevent or reverse prolonged tolerance in vivo, we gave Aoah−/− mice LPS i.p. on day 0, followed by rhAOAH or carrier protein BSA i.p. daily from day 1 to day 13. Peritoneal cells were harvested on day 14, plated, and adherent macrophages were rechallenged ex vivo with LPS. LPS-stimulated RANTES and IL-6 were at naïve Aoah−/− macrophage levels in macrophages from animals that had received rhAOAH treatment (Fig. 9A–C). TNF production is the most sensitively reprogrammed component of tolerance in these cells; here the TNF level in culture medium overlying macrophages from LPS-exposed rAOAH-treated mice was significantly lower than the naïve macrophage level but 10-fold higher than the levels produced by macrophages from mice that received carrier protein BSA instead of rhAOAH. Recombinant AOAH was thus able to ameliorate prolonged tolerance in vivo in Aoah−/− animals. Treatment with IFN-γ or antibody to IL-10 receptor did not rescue Aoah−/− animals from prolonged endotoxin tolerance (data not shown), in line with the conclusion that bioactive LPS plays a dominant role in maintaining prolonged tolerance in vivo.

Bottom Line: Mice that are unable to inactivate LPS, in contrast, remain tolerant for several months; during this time they respond sluggishly to Gram-negative bacterial challenge, with high mortality.We show here that prolonged macrophage reprogramming is maintained in vivo by the persistence of stimulatory LPS molecules within the cells' in vivo environment, where naïve cells can acquire LPS via cell-cell contact or from the extracellular fluid.Measures that disable microbial molecules might enhance resolution of tissue inflammation and help restore innate defenses in individuals recovering from many different infectious diseases.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America. Lum3@niaid.nih.gov

ABSTRACT
Measures that bolster the resolution phase of infectious diseases may offer new opportunities for improving outcome. Here we show that inactivation of microbial lipopolysaccharides (LPS) can be required for animals to recover from the innate immune tolerance that follows exposure to Gram-negative bacteria. When wildtype mice are exposed to small parenteral doses of LPS or Gram-negative bacteria, their macrophages become reprogrammed (tolerant) for a few days before they resume normal function. Mice that are unable to inactivate LPS, in contrast, remain tolerant for several months; during this time they respond sluggishly to Gram-negative bacterial challenge, with high mortality. We show here that prolonged macrophage reprogramming is maintained in vivo by the persistence of stimulatory LPS molecules within the cells' in vivo environment, where naïve cells can acquire LPS via cell-cell contact or from the extracellular fluid. The findings provide strong evidence that inactivation of a stimulatory microbial molecule can be required for animals to regain immune homeostasis following parenteral exposure to bacteria. Measures that disable microbial molecules might enhance resolution of tissue inflammation and help restore innate defenses in individuals recovering from many different infectious diseases.

Show MeSH
Related in: MedlinePlus