Abnormal cell responses and role of TNF-α in impaired diabetic wound healing

Abstract

Impaired diabetic wound healing constitutes a major health problem. The impaired healing is caused by complex factors such as abnormal keratinocyte and fibroblast migration, proliferation, differentiation, and apoptosis, abnormal macrophage polarization, impaired recruitment of mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs), and decreased vascularization. Diabetes-enhanced and prolonged expression of TNF- α also contributes to impaired healing. In this paper, we discuss the abnormal cell responses in diabetic wound healing and the contribution of TNF- α .

Figure 1

Mechanisms of impaired diabetic wound healing. The normal wound-healing process is initiated by the integration of multiple intercellular signals (cytokines and chemokines) released by keratinocytes, fibroblasts, endothelial cells, macrophages, platelets, etc. In diabetes, inflammatory cytokines and chemokines are elevated, such as TNF-α, IL-1, IL-6, CCL2, CCL3, CCL4, CXCL1, CXCL5, and CXCL8. Cellular processes affected by diabetes include abnormal keratinocyte and fibroblast migration, proliferation, and enhanced apoptosis; abnormal macrophage polarization (increased proinflammatory M1 macrophages and decreased anti-inflammatory M2 macrophages); impaired recruitment of mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs), and decreased vascularization.

Figure 2

Model of TNF-α on regulation of inflammation, immue response, migration, and differentiation. TNF-α induces cell apoptosis via caspase pathway, and it negatively regulates cell migration by increasing the level of Smad 7 and inhibiting the activation of the Smad 2/3. TNF-α also induces NF-κB activation to enhance inflammatory responses.