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Regulation of glycolysis and the Warburg effect in wound healing
Roohi Vinaik, … , Abdikarim Abdullahi, Marc G. Jeschke
Roohi Vinaik, … , Abdikarim Abdullahi, Marc G. Jeschke
Published August 4, 2020
Citation Information: JCI Insight. 2020;5(17):e138949. https://doi.org/10.1172/jci.insight.138949.
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Research Article Inflammation Therapeutics

Regulation of glycolysis and the Warburg effect in wound healing

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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.

Authors

Roohi Vinaik, Dalia Barayan, Christopher Auger, Abdikarim Abdullahi, Marc G. Jeschke

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Figure 2

Burn patients who develop keloids have prior indications of altered glucose metabolism.

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Burn patients who develop keloids have prior indications of altered gluc...
(A) GLUT1 gene expression in burn and normal skin samples obtained from burn patients before the development of keloids indicates higher expression compared with typical values seen in nonkeloid patients (≥ 2 SDs above mean). Similarly, keloids exhibited increased Glut1 staining. (B) Immunohistochemical staining for Glut1 in skin from keloid patients indicates more Glut1+ cells in basal epidermal and dermal layers compared with nonkeloid counterparts (normal skin, top panel; burn skin 7–10 days after burn, bottom panel). Individual data points (X) denote gene expression values for individual patients. Values are presented as mean ± SEM. Experiments were conducted twice. One-way ANOVA; **P < 0.01 burn versus normal.

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