GDF15 Is an Inflammation-Induced Central Mediator of Tissue Tolerance

  • Cell. 2019 Aug 22;178(5):1231-1244.e11. doi: 10.1016/j.cell.2019.07.033.
Harding H Luan  1 ,  Andrew Wang  2 ,  Brandon K Hilliard  3 ,  Fernando Carvalho  1 ,  Connor E Rosen  1 ,  Amy M Ahasic  4 ,  Erica L Herzog  4 ,  Insoo Kang  5 ,  Margaret A Pisani  4 ,  Shuang Yu  1 ,  Cuiling Zhang  3 ,  Aaron M Ring  1 ,  Lawrence H Young  6 ,  Ruslan Medzhitov  7
Affiliations
  • 1. Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 2. Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Medicine (Rheumatology), Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: [email protected].
  • 3. Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Medicine (Rheumatology), Yale University School of Medicine, New Haven, CT 06520, USA.
  • 4. Department of Medicine (Pulmonary, Critical Care and Sleep), Yale University School of Medicine, New Haven, CT 06520, USA.
  • 5. Department of Medicine (Rheumatology), Yale University School of Medicine, New Haven, CT 06520, USA.
  • 6. Department of Medicine (Cardiology), Yale University School of Medicine, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 7. Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: [email protected].
PMID: 31402172 DOI: 10.1016/j.cell.2019.07.033
Abstract

Growth and differentiation factor 15 (GDF15) is an inflammation-associated hormone with poorly defined biology. Here, we investigated the role of GDF15 in Bacterial and viral infections. We found that inflammation induced GDF15, and that GDF15 was necessary for surviving both Bacterial and viral infections, as well as sepsis. The protective effects of GDF15 were largely independent of pathogen control or the magnitude of inflammatory response, suggesting a role in disease tolerance. Indeed, we found that GDF15 was required for hepatic sympathetic outflow and triglyceride metabolism. Failure to defend the lower limit of plasma triglyceride levels was associated with impaired cardiac function and maintenance of body temperature, effects that could be rescued by exogenous administration of lipids. Together, we show that GDF15 coordinates tolerance to inflammatory damage through regulation of triglyceride metabolism.

Keywords
GDF15; adrenergic signaling; cardioprotection; inflammation; metabolism; neuroimmunology; sepsis; tolerance; triglyceride.