From:  Immunomodulation: scope and limitations in promoting diabetic foot ulcer healing

 Immune response and molecular mechanisms involved in phases of wound healing.

Wound healing phaseInvolved in molecular mechanisms, immune cells, and other cell types
Hemostasis (minutes to hours)

  • Platelets aggregate, releasing clotting factors.

  • Activation of the coagulation cascade and thrombus formation.

  • Release of growth factors (PDGF, VEGF, TGF-β) and chemokines from platelets.

  • Complement activation increases vascular permeability.

  • Tissue-resident cells (e.g., mast cells) release mediators like histamine, promoting early vasodilation and mediating the influx of inflammatory cells.

  • Immune cells (innate and adaptive) recruitment and activation

  • Stage for acute inflammation.

Inflammatory phase (hours to days)

  • Neutrophils (0–24 hours) are the first responders, clearing bacteria and debris by releasing reactive oxygen species (ROS) and proteases.

  • M1 macrophages (24 hours to days) replace neutrophils and are critical for wound healing, acting as “sentinels” that clear dead cells and release growth factors to initiate repair.

  • Resident skin cells activate immune cells, which secrete pro-inflammatory cytokines, thereby activating signaling cascades that regulate cell survival and metabolism.

  • Keratinocytes secrete pro-inflammatory cytokines, which recruit macrophages that also secrete pro-inflammatory cytokines.

  • Mast cells and T-cells also contribute to modulating the inflammatory environment.

Proliferative phase (days to weeks)

  • Macrophages switch from a pro-inflammatory (M1) to an anti-inflammatory (M2) phenotype, promoting angiogenesis, fibroblast activation, and collagen deposition.

  • Granulation tissue formation consists of fibroblasts, granulocytes, macrophages, blood vessels, and collagen bundles.

  • Angiogenesis is regulated by growth factors (VEGF, FGF, TGF-β, PDGF, and angiopoietin) secreted by fibroblasts, platelets, macrophages, and keratinocytes.

  • Re-epithelialization is promoted by growth factors (KGF, EGF, TGF-β) and keratinocyte migration/proliferation.

Remodeling phase (weeks to months)

  • The immune response subsides, reducing inflammation, allowing for ECM reorganization, and strengthening tissue.

  • Decreased neo-vascularization.

  • Granulation tissue is replaced by scar tissue.

  • Type III collagen is replaced by type I collagen.

  • Excess fibroblasts, macrophages, and vessels undergo apoptosis, resulting in a relatively acellular, avascular scar.

Return to article view

EGF: epidermal growth factor; FGF: fibroblast growth factor; VEGF: vascular endothelial growth factor; TGF-β: transforming growth factor beta; PDGF: platelet-derived growth factor; KGF: keratinocyte growth factor; ECM: extracellular matrix.