Methylglyoxal deteriorates macrophage efferocytosis in diabetic wounds through ROS-induced ubiquitination degradation of KLF4
Hanting Zhu, Wenao Wang, Jiajun Zhu, Xuelian Chen, Jizhuang Wang, Jiaqiang Wang, Dan Liu, Peilang Yang, Yan Liu
Abstract
Diabetic wounds are a leading cause of disability and mortality in patients with diabetes, and persistent low-grade inflammation plays a significant role in their pathogenesis. Methylglyoxal (MGO), an active product of glucose metabolism, often induces chronic inflammation and is considered a major risk factor in the healing of diabetic wounds. Efferocytosis, the process by which macrophages clear apoptotic cells, is crucial for terminating the inflammatory response and tissue repair. However, the role of MGO in macrophage efferocytosis remains unclear. This study aimed to investigate whether MGO regulates macrophage efferocytosis and the underlying mechanisms. In this study, we observed impaired efferocytosis in diabetic wounds, leading to the accumulation of apoptotic neutrophils and a relative deficiency of M2 macrophages, with MGO being a significant cause. MGO promotes the production of ROS, which not only activates the MAPK p38 pathway, but also upregulates the transcription of the E3 ubiquitin ligase FBXO32, catalyzing the ubiquitination of the transcription factor KLF4 and suppressing the transcription of MerTK mRNA, thereby affecting the phagocytic function of macrophages. Inhibition of the MAPK p38 pathway or knockdown of FBXO32 reduced the ubiquitination and degradation of KLF4, thus mitigating the impairment of efferocytosis caused by oxidative stress. This study reveals the mechanism by which MGO inhibits efferocytosis in diabetic wounds, providing a new target and theoretical basis for the treatment of chronic diabetic wounds. • Methylglyoxal (MGO) impairs macrophage efferocytosis in diabetic wounds. • Efferocytosis inhibition disrupts M1 to M2 macrophage transition in diabetic wounds. • MGO increases ROS production which phosphorylates p38 MAPK and upregulates FBXO32. • FBXO32 ubiquitinates transcription factor KLF4, suppressing MerTK transcription. • A new target and theoretical basis for the treatment of chronic diabetic wounds.