Naringenin Accelerates Diabetic Wound Healing via Regulating Macrophage M2 Polarization and Efferocytosis

Abstract

Diabetic wounds that do not heal are a significant complication of diabetes, among which chronic inflammation serves as a critical contributing factor. The regulation of inflammation in diabetic wound healing is significantly impacted by macrophages via their efferocytosis and polarization activities. Naringenin is a natural flavonoid that has been recognized for its anti-inflammatory effects and potential therapeutic benefits in treating diabetes-related conditions. This research examines how naringenin impacts non-healing diabetic wounds and delves into the mechanisms behind it. The study involved male C57BL/6 mice categorized into three groups: control, diabetes, and diabetes with naringenin treatment. Researchers assessed the effect of naringenin on wound healing by applying it topically to a diabetic mouse model induced with streptozotocin (STZ). Moreover, researchers used THP-1 cells in vitro to examine the effects of naringenin on the polarization of macrophages to the M2 phenotype and their efferocytosis. Subsequently, the effects of naringenin treatment were assessed using RT-qPCR, western blot, immunofluorescence, and additional assays. Animal experiments demonstrated that naringenin significantly accelerated diabetic wound healing. Naringenin decreased inflammatory cytokines, promoted M2 macrophage polarization, and enhanced macrophage efferocytosis in wound healing. Consistent with animal studies, naringenin inhibits macrophage M1 polarization while augmenting M2 polarization in THP-1 cells, with ML385 specifically rescuing the M1 suppression. In addition, naringenin also promoted macrophage efferocytosis in a THP-1/Jurkat apoptotic co-culture mode. Naringenin significantly promotes diabetic wound healing via ameliorating wound inflammation and exerts its therapeutic effects through promoting M2 macrophages and enhancing efferocytosis.