Sulforaphane promotes diabetic wound healing by regulating macrophage efferocytosis and polarization

Background: Delayed wound healing frequently occurs as a complication of diabetes. Diabetic wounds that are difficult to heal are associated with chronic, persistent inflammation, characterized by impaired efferocytosis and a sustained pro-inflammatory state of macrophages at the wound site. Sulforaphane (SFN), a bioactive compound found in Cruciferous vegetables, possesses anti-inflammatory and antioxidant activities. Numerous studies have shown that SFN can inhibit various inflammatory diseases such as atherosclerosis and psoriasis; however, its potential in treating diabetic wounds remains unknown.

Purpose: This study investigates the effects and potential mechanisms of SFN on diabetic wound healing.

Methods: Network pharmacology approaches were employed to identify potential targets of SFN for diabetic wound treatment. Additionally, an STZ-induced diabetic mouse model (C57/B6) was used in in vivo studies to examine SFN's impact on diabetic wound healing. Simultaneously, immunofluorescence staining, immunohistochemical staining, Western blotting, and qPCR analysis were employed to detect phenotypes associated with macrophage efferocytosis and M2 polarization. Subsequently, the mechanism underlying SFN treatment was explored through in vitro experiments utilizing the THP-1 human monocyte cell line.

Results: The results demonstrated that topical SFN application accelerated wound healing in diabetic mice, partly through the enhancement of impaired macrophage efferocytosis and the promotion of M2 macrophage polarization, thereby reducing the inflammatory response at the wound site. SFN promoted the phagocytosis of apoptotic Jurkat cells by THP-1 differentiated macrophages, reducing the resulting inflammatory response. Mechanistic studies revealed that SFN promotes macrophage efferocytosis by activating nuclear factor E2-related factor 2 (Nrf2), leading to upregulation of heme oxygenase 1 (HO-1) expression and subsequent enhancement of Mer proto-oncogene tyrosine kinase (MERTK), a recognition receptor for efferocytosis. Furthermore, SFN enhanced macrophage polarization toward the M2 phenotype and reduced the lipopolysaccharide (LPS)-induced inflammatory response in vitro.

Conclusion: These data suggest that SFN could serve as an effective adjunct or novel therapeutic agent for treating chronic non-healing wounds in diabetes.

Diabetic wound healing; Efferocytosis; Inflammation; Macrophage polarization; Sulforaphane.