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NAD+-DEPENDENT SIRT1 REPROGRAMS CD11C+ DENDRITIC CELLS AND CD4+ T CELLS TO CONTROL IMMUNE POLARITY DURING SEPSIS

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abstract
There is a deficit in the understanding of immune response polarity during sepsis and acute inflammation. Skewing of the polarity can lead to immunometabolic dysfunction, organ failure, and death from sepsis. Sirtuins are known regulators of immunity and have been shown to play a pivotal role in regulating innate immune responses. However, their role in adaptive immune responses remains uncertain. The findings presented in this body of research indicate several novel aspects of T cell programming during sepsis and, for the first time, bridge sepsis effects on innate and adaptive immunity. In our model, SIRT1 activation acts through CD11c+ tolerogenic dendritic cells and their support of TGFβ and IL-10 secretions from CD4+ TReg cells as contributors to sepsis immunosuppression. That SIRT1 drives this innate and adaptive immune link is supported by the ability of SIRT1-specific inhibitor EX527 to reverse this process. As a result, both the CD11c+ dendritic cell and the CD4+ TH1 cell functions are reprogrammed to a pro-immune state to support infection resolution and promote sepsis survival. We predict that SIRT1 inhibition in failing organs like liver, heart, and kidney may also restore the anabolic needs of these organs to recover their function as part of the unifying concept of regulating homeostasis during sepsis. Since there are presently no mechanism-based targets for sepsis, this study may have high impact on how sepsis kills, how it survives, and how it may be treated by unifying homeostasis principles. As such, our study may have both significant clinical and financial implications to our health care system.
subject
acute inflammation
adaptive immunity
dendritic cell
sepsis
SIRT1
T regulatory cell
contributor
Martin, Ayana (author)
McCall, Charles E (committee chair)
Alexander-Miller, Martha A (committee member)
Vachharajani, Vidula (committee member)
Brown, Candice (committee member)
Seeds, Michael (committee member)
date
2017-08-22T08:35:21Z (accessioned)
2017-08-22T08:35:21Z (available)
2017 (issued)
degree
Molecular Medicine and Translational Science (discipline)
identifier
http://hdl.handle.net/10339/86333 (uri)
language
en (iso)
publisher
Wake Forest University
title
NAD+-DEPENDENT SIRT1 REPROGRAMS CD11C+ DENDRITIC CELLS AND CD4+ T CELLS TO CONTROL IMMUNE POLARITY DURING SEPSIS
type
Dissertation

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