Regulation of glycolysis and the Warburg effect in wound healing

JCI Insight. 2020 Sep 3;5(17):e138949. doi: 10.1172/jci.insight.138949.

Abstract

One of the most significant adverse postburn responses is abnormal scar formation, such as keloids. Despite its prolificacy, the underlying pathophysiology of keloid development is unknown. We recently demonstrated that NLRP3 inflammasome, the master regulator of inflammatory and metabolic responses (e.g., aerobic glycolysis), is essential for physiological wound healing. Therefore, burn patients who develop keloids may exhibit altered immunometabolic responses at the site of injury, which interferes with normal healing and portends keloid development. Here, we confirmed keloid NLRP3 activation (cleaved caspase-1 [P < 0.05], IL-1β [P < 0.05], IL-18 [P < 0.01]) and upregulation in Glut1 (P < 0.001) and glycolytic enzymes. Burn skin similarly displayed enhanced glycolysis and Glut1 expression (P < 0.01). However, Glut1 was significantly higher in keloid compared with nonkeloid burn patients (>2 SD above mean). Targeting aberrant glucose metabolism with shikonin, a pyruvate kinase M2 inhibitor, dampened NLRP3-mediated inflammation (cleaved caspase-1 [P < 0.05], IL-1β [P < 0.01]) and improved healing in vivo. In summary, burn skin exhibited evidence of Warburg-like metabolism, similar to keloids. Targeting this altered metabolism could change the trajectory toward normal scarring, indicating the clinical possibility of shikonin for abnormal scar prevention.

Keywords: Glucose metabolism; Inflammation; Skin; Therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Burns / complications*
  • Case-Control Studies
  • Female
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 1 / metabolism
  • Glycolysis*
  • Humans
  • Inflammasomes
  • Inflammation / etiology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation / prevention & control*
  • Inflammation Mediators
  • Keloid / etiology
  • Keloid / metabolism
  • Keloid / pathology
  • Keloid / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • NLR Family, Pyrin Domain-Containing 3 Protein / physiology*
  • Naphthoquinones / pharmacology
  • Pyruvate Kinase / antagonists & inhibitors
  • Skin / drug effects*
  • Wound Healing*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Glucose Transporter Type 1
  • Inflammasomes
  • Inflammation Mediators
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Naphthoquinones
  • shikonin
  • Pyruvate Kinase