Targeting phenylpyruvate restrains excessive NLRP3 inflammasome activation and pathological inflammation in diabetic wound healing.
Cell Rep Med
; 4(8): 101129, 2023 08 15.
Article
in En
| MEDLINE
| ID: mdl-37480849
ABSTRACT
Moderate inflammation is essential for standard wound healing. In pathological conditions, such as diabetes, protracted and refractory wounds are associated with excessive inflammation, manifested by persistent proinflammatory macrophage states. However, the mechanisms are still unclear. Herein, we perform a metabolomic profile and find a significant phenylpyruvate accumulation in diabetic foot ulcers. Increased phenylpyruvate impairs wound healing and augments inflammatory responses, whereas reducing phenylpyruvate via dietary phenylalanine restriction relieves uncontrolled inflammation and benefits diabetic wounds. Mechanistically, phenylpyruvate is ingested into macrophages in a scavenger receptor CD36-dependent manner, binds to PPT1, and inhibits depalmitoylase activity, thus increasing palmitoylation of the NLRP3 protein. Increased NLRP3 palmitoylation is found to enhance NLRP3 protein stability, decrease lysosome degradation, and promote NLRP3 inflammasome activation and the release of inflammatory factors, such as interleukin (IL)-1ß, finally triggering the proinflammatory macrophage phenotype. Our study suggests a potential strategy of targeting phenylpyruvate to prevent excessive inflammation in diabetic wounds.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Diabetes Mellitus
/
NLR Family, Pyrin Domain-Containing 3 Protein
Limits:
Humans
Language:
En
Journal:
Cell Rep Med
Year:
2023
Document type:
Article
Affiliation country: