Cytosolic LPS Activates Caspase-11: Implications for Innate Immunity and Management of Septic Shock Public Deposited

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  • March 19, 2019
Creator
  • Hagar, Jon
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Caspases are either apoptotic or inflammatory. Amongst inflammatory caspases, caspase-1 and -11 trigger pyroptosis, a form of programmed cell death. Whereas both can be detrimental in inflammatory disease, only caspase-1 has an established protective role during infection. In Chapter 2, we report that caspase-11 is required for innate immunity to cytosolic, but not vacuolar, Gram-negative bacteria. Burkholderia species that naturally invade the cytosol triggered caspase-11, as did cytosol invading mutants of the normally vacuolar pathogens Salmonella typhimurium and Legionella pneumophila. This pathway protected mice from lethal challenge with B. thailandensis and B. pseudomallei. Thus, caspase-11 is critical for surviving exposure to ubiquitous environmental pathogens. During endotoxemia, excessive caspase-11 activation causes shock. In Chapter 3, we report that contamination of the cytoplasm by lipopolysaccharide (LPS) is the signal that triggers caspase-11 activation in mice. Priming the caspase-11 pathway in vivo resulted in extreme sensitivity to subsequent LPS challenge in both wild type and Tlr4-deficient mice, whereas caspase 11-deficient mice were relatively resistant. Together, our data reveal a new pathway for detecting cytoplasmic LPS. Critically ill patients typically present with hyperglycemia as a result of stress hormone and inflammatory cytokine signaling, which induces peripheral insulin resistance over time. Treating hyperglycemia with insulin improves the survival of patients in intensive care units (ICU); however, extreme controversy has surrounded how stringently blood glucose should be controlled. Amongst subgroups of ICU patients, those with sepsis are particularly prone to hypoglycemia during insulin therapy, which is a risk factor for death. Why sepsis predisposes to hypoglycemia remains unknown. In Chapter 4, we show that co-delivery of insulin with otherwise sublethal doses of LPS induced lethal hypoglycemic shock in mice within 1-2 hours. LPS impaired clearance of insulin, which amplified insulin receptor and AKT signaling. Our results raise the possibility that septic patients have impaired insulin clearance, which could increase their susceptibility to hypoglycemia during insulin therapy. Factoring differential insulin clearance into insulin administration protocols could minimize the risk of hypoglycemia, allowing safer study of whether intensive glucose control confers a survival benefit relative to conventional glucose control.
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  • In Copyright
Advisor
  • Miao, Edward
  • Cairns, Bruce
  • Moorman, Nathaniel
  • Su, Lishan
  • Ting, Jenny P.-Y.
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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