The goal of this proposal is to determine how alterations in mitochondrial metabolism and bioenergetics influence the immunosuppressive phase of sepsis. Sepsis incidence is rising, there are no specific therapies, and most deaths occur during the phase of immunosuppression that follows hyperinflammation. We discovered using a cell-based model of sepsis and human sepsis blood leukocytes that NAD+-dependent deacetylase Sirtuin 1 (Sirt1) activates NF-kB factor RelB to switch proinflammation to immunosuppression, reduce glucose-dependent anabolic pathways and increase catabolic lipolysis and mitochondrial fatty acid oxidation. We also find that Sirt1-activated RelB induces expression of mitochondrial regulator Sirt3, which as a mitochondrial protein promotes catabolic fatty acid oxidation and mitochondrial respiration. Moreover, RelB translocates to mitochondria, binds mitochondrial promoter DNA, and increases transcription of mitochondrial genes. Remarkably, Sirt1 inhibition markedly improves survival of septic mice when administered during the immunosuppressive phase. Substantial data support that switching from anabolism to catabolism can compromise glucose-dependent effector immune responses. Based on these collective data: This proposal will test the hypothesis that protracted Sirt1 activation adversely affects sepsis outcome through a Sirt1-RelB-Sirt3 nuclear-mitochondrial axis (here, called the Sirt1 axis) to decrease net anabolic and increase net catabolic metabolism in myeloid-derived innate immune cells. We have designed 3 aims to explore this new concept:
Aim 1 : Determine whether Sirt1 axis activation alters mitochondrial metabolism and bioenergetics during sepsis immunosuppression.
Aim 2 : Determine how mitochondrial gene expression and the electron transport chain are regulated by the Sirt1 axis during the immunosuppressed phase of sepsis.
Aim 3 : Define how Sirt1 and RelB regulate Sirt3 expression. Approach: Cell-based, murine and human sepsis responses will be investigated using state-of-the art biochemical, molecular cell biology, and genetics tools. Impact: Completing these aims will define the role of the Sirt1 axis in sepsis immunosuppression of innate immunity, identify precise mitochondrial and nuclear processes controlled by the Sirt1 axis, and introduce a new way to treat the disease by rebalancing the net function of the immunometabolic axis.

Public Health Relevance

Sepsis is a highly lethal disease with major global health and economic impact and without effective drugs. This translational research will identify how sepsis specifically modifies mitochondrial physiology and whether rebalancing these changes improves prognosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM102497-01A1
Application #
8696501
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Dunsmore, Sarah
Project Start
2014-08-05
Project End
2018-04-30
Budget Start
2014-08-05
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$292,600
Indirect Cost
$102,600
Name
Wake Forest University Health Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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McClure, Clara; Ali, Ekram; Youssef, Dima et al. (2016) NFI-A disrupts myeloid cell differentiation and maturation in septic mice. J Leukoc Biol 99:201-11
Wang, Xianfeng; Buechler, Nancy L; Martin, Ayana et al. (2016) Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice. PLoS One 11:e0160431
Millet, Patrick; Vachharajani, Vidula; McPhail, Linda et al. (2016) GAPDH Binding to TNF-α mRNA Contributes to Posttranscriptional Repression in Monocytes: A Novel Mechanism of Communication between Inflammation and Metabolism. J Immunol 196:2541-51
Ding, Jingzhong; Reynolds, Lindsay M; Zeller, Tanja et al. (2015) Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease. Diabetes 64:3464-74
Wang, Xianfeng; Buechler, Nancy L; Yoza, Barbara K et al. (2015) Resveratrol attenuates microvascular inflammation in sepsis via SIRT-1-Induced modulation of adhesion molecules in ob/ob mice. Obesity (Silver Spring) 23:1209-17
Smith, Lane M; Wells, Jonathan D; Vachharajani, Vidula T et al. (2015) SIRT1 mediates a primed response to immune challenge after traumatic lung injury. J Trauma Acute Care Surg 78:1034-8
Liu, Tie Fu; Vachharajani, Vidula; Millet, Patrick et al. (2015) Sequential actions of SIRT1-RELB-SIRT3 coordinate nuclear-mitochondrial communication during immunometabolic adaptation to acute inflammation and sepsis. J Biol Chem 290:396-408
Reynolds, Lindsay M; Ding, Jingzhong; Taylor, Jackson R et al. (2015) Transcriptomic profiles of aging in purified human immune cells. BMC Genomics 16:333

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