Growth and Differentiation Factor 15 (GDF15) is highly induced in virtually all inflammatory conditions in humans, including sepsis, cancer and autoimmunity, but its role in the inflammatory response has been unclear. This proposal seeks to understand the role of Growth and Differentiation Factor 15 (GDF15) in mediating protection in sepsis. Preliminary data for this proposal reveals that GDF15 is induced specifically in models of acute infection/inflammation but not other environmental stress conditions and achieves nanogram levels in circulation. The GDF15 receptor, glial cell-lone derived neurotrophic factor receptor alpha-like (GFRAL), was found only in the hindbrain and not induced by inflammation. Blockade of GDF15 led to enhanced mortality in multiple models of sepsis, including lipopolysaccharide (LPS), cecal-ligation puncture (CLP), Poly(I:C), and influenza. Conversely, late administration of recombinant GDF15 led to protection. GDF15 inhibition did not affect inflammatory magnitude or pathogen control. However, GDF15 blockade led to an impairment in the ability of mice to switch to an oxidative phosphorylation state. There was no difference in ketonemia or plasma free fatty acids but a significant decrease in circulating plasma triglycerides. We also found that blockade of GDF15 led to enhanced cardiotoxicity, without a difference in overall hemodynamic control. Thus, GDF15 is a tissue protective hormone. This proposal seeks to test the idea that GDF15 is an adaptive cytokine produced by macrophages in response to acute inflammation, which mediates cardioprotection by controlling triglyceride metabolism via sympathetic innervation.

Public Health Relevance

Tissue damage and subsequent organ failure in sepsis, such as septic cardiomyopathy, is mediated by inflammatory damage and is the cause of mortality and morbidity. We found that GDF15 plays a role in surviving sepsis by organizing organismal metabolic state thereby maintaining tissue tolerance to inflammation. Identifying pathways that can enhance protective tissue responses to inflammation will contribute to therapeutics that can prevent organ dysfunction and improve survival.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI144152-01
Application #
9716169
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Jiang, Chao
Project Start
2019-01-01
Project End
2023-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520