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4-Octyl Itaconate Promotes Diabetic Wound Healing by Enhancing Pro-Resolving Macrophages via the
Mengqin Tu1,2,3,4, Xiaoli Zou1,2,3,4, Xiaozhen Tan1,2,4,5
1Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
Backgruound:
Diabetic foot ulcers are a severe diabetic complication characterized by poor healing. Itaconate, a tricarboxylic acid cycle byproduct, has been shown to improve wound healing. This study investigated the potential of 4-octyl itaconate (4-OI), an esterified derivative of itaconate, to modulate efferocytosis and macrophage pro-resolving function to promote diabetic wound healing.
Methods:
A diabetic mouse wound model was used. For in vitro analysis, RAW264.7 macrophages and apoptotic Jurkat cells were cocultured under high glucose conditions (HG, 30 mM). To further evaluate the roles of macrophages, monocarboxylate transporter 1 (MCT1), and lactate in 4-OI-promoted diabetic wound healing, we used clodronate-liposomes (CLD-Lipo) to deplete macrophages, AZD3965 as an MCT1 inhibitor, and telmisartan to validate our hypothesis.
Results:
In diabetic mice, impaired clearance of apoptotic neutrophils and persistent M1 activation delayed wound healing. 4-OI improved diabetic wound repair by enhancing efferocytosis, shifting macrophages toward an M2 pro-resolving phenotype, and boosting angiogenesis. 4-OI showed a protective effect mediated by macrophages, while endothelial cells and neutrophils also played synergistic roles in diabetic wound healing. Moreover, 4-OI upregulated MCT1, which, in turn, increased the release of lactate triggered by efferocytosis at the wound site. Lastly, we confirmed that the pro-resolving effects of 4-OI onmacrophage function were mediated by promoting pro-resolving macrophage proliferation and polarization via efferocytosis-induced lactate release and subsequent activation of G protein-coupled receptor 132 (GPR132).
Conclusion:
4-OI promotes diabetic wound healing through macrophage-dependent and macrophage-independent mechanisms. Moreover, the protective effect of 4-OI on macrophages was mediated through MCT1-mediated lactate release triggered by efferocytosis and subsequent GPR 132 activation.
