Lean Adipose Tissue Macrophage Derived Exosome Confers Immunoregulation to Improve Wound Healing in Diabetes

Abstract

Abstract Chronic non-healing wounds, an important complication of diabetes, are associated with increased mortality in patients afflicted with this disease. Excessive accumulation of M1 macrophages in diabetic wounds promotes inflammation and results in dysregulated tissue repair. Adipose tissue macrophages (ATMs) derived from healthy lean donors have the abilities to improve glucose tolerance and insulin sensitivity, and modulate inflammation. MiRNAs (miRs), which can be packaged into exosomes (Exos) and secreted from cells, serve as essential regulators of macrophage polarization. Here, we reveal that adipose tissue macrophages (ATMs) isolated from lean mice secrete miR-containing Exos, which modulate macrophage polarization and promote rapid diabetic wound healing when administered to diabetes-prone db/db mice. MiRs sequence of tissue samples from wounds treated with Exos secreted by lean ATMs (ATM-Exos) revealed that miR-222-3p was upregulated. Further analyses showed that inhibition of miR-222-3p using miR inhibitor impaired the macrophage-reprogramming effect of lean ATM-Exos. In the excisional skin wound mouse model, locally inhibiting miR-222-3p disrupted healing dynamics and failed to modulate macrophage polarization. Mechanistic studies revealed a link between miR-222-3p; Bcl2l11/Bim, an inflammatory response effector; macrophage polarization; and diabetic wound healing. In summary, lean ATM-Exos act as positive regulators of macrophage polarization by regulating miR levels in wounds and accelerating wound healing and thus have important implications for wound management in diabetes.