The mechanism of action of GLUT1 in promoting NETs-mediated impairment of macrophage phenotypic switching based on macrophage-fibroblast interplay.

This study explored the mechanism by which glucose transporter type 1 (GLUT1) promotes neutrophil extracellular trap (NET)-mediated macrophage phenotype conversion in a high-glucose environment, based on the interaction between fibroblasts and macrophages. We demonstrated that GLUT1 plays an important role in immune cell-fibroblast crosstalk. High glucose induces GLUT1 to upregulate high mobility group box 1 (HMGB1) levels, thereby promoting NET release and macrophage M1 polarization. Addition of a NET inhibitor promoted macrophage M2 polarization and alleviated the impaired macrophage phenotype conversion. Additionally, overexpression of Glut1 enhanced the expression of inflammatory factors tumor necrosis factor alpha (TNF-α) and interleukin beta (IL-1β), leading to inflammatory damage to fibroblasts, which was reversed significantly by inhibiting NETs . The results indicated that GLUT1 mediates the crosstalk between NETs, macrophage phenotype conversion impairment, and inflammatory damage in fibroblasts. This study emphasizes the importance of GLUT1 in the interaction between immune cells and fibroblasts, and its regulatory role in the impairment of NET-mediated macrophage phenotype conversion. These findings suggest that the regulatory mechanisms between HMGB1 and NETs in a high-glucose environment might provide potential therapeutic targets to treat diabetic wounds.