Restoring Prohealing/Remodeling-Associated M2a/c Macrophages Using ON101 Accelerates Diabetic Wound Healing

Area of Science:

• Immunology
• Wound Healing
• Cell Biology

Background:

• Diabetic wounds suffer from chronic inflammation and poor healing due to persistent M1 macrophage activity and impaired M2 macrophage transition.
• This macrophage imbalance hinders tissue proliferation and remodeling, complicating diabetic foot ulcer (DFU) treatment.

Purpose of the Study:

• To investigate the therapeutic potential of ON101, a plant-derived compound, in modulating macrophage polarization for enhanced diabetic wound healing.
• To elucidate the mechanisms by which ON101 influences M1-to-M2 macrophage polarization and its impact on inflammatory gene expression in a diabetic mouse model.

Main Methods:

• Topical ON101 treatment was applied to a diabetic mouse model, and macrophage populations (M1, M2a, M2c) were analyzed.
• In vitro studies utilized macrophage-polarizing models to assess ON101's direct effects on macrophage polarization and cytokine production.
• Gene expression analysis (GCSF, CXCL3) in adipocyte progenitor cells and the effects of recombinant proteins were evaluated.

Main Results:

• ON101 treatment increased M2c-like (CD163+, CD206+) cells and decreased M1-like cells in diabetic mice.
• In vitro, ON101 directly suppressed M1 macrophage polarization and pro-inflammatory cytokines.
• ON101-treated cells promoted M2 macrophage markers and stimulated GCSF and CXCL3 expression, which enhanced M2 macrophage polarization.

Conclusions:

• ON101 effectively suppresses M1 macrophages and promotes M2 macrophage polarization, crucial for resolving inflammation in diabetic wounds.
• The plant-based therapeutic ON101 facilitates diabetic wound healing by modulating macrophage phenotypes and stimulating key regulatory genes like GCSF and CXCL3.