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.
Highlights
Wound healing is a complex and carefully coordinated physiologic response to a cutaneous injury inflicted in conditions such as surgery, trauma, or burns
A similar metabolic profile is seen in nonkeloid hyperproliferative conditions that result in an analogous excessive extracellular matrix (ECM) production to keloids [6]
We determined if NLRP3-mediated inflammation is still activated beyond this time point in keloids by measuring protein levels of cleaved caspase-1 and IL-1β in keloids compared with burn skin (7–10 days after burn, average age 53 years and total body surface area [TBSA] 39%) and normal skin (Figure 1, A and B)
Summary
Wound healing is a complex and carefully coordinated physiologic response to a cutaneous injury inflicted in conditions such as surgery, trauma, or burns Deregulation of this process following insult to the reticular dermis can result in aberrant scar formation, such as keloids [1,2,3]. Despite their common occurrence, keloids remain one of the most challenging conditions to successfully treat and are associated with pruritus, pain, and contractures, often leaving a significant functional and psychosocial impact on patients. These human and murine fibrosis models demonstrate an upregulation in glycolytic enzymes and glucose transporters coupled with increased lactate production, highlighting a similar pathological behavior to keloid and tumor cells [6, 7]
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