Abstract
Persistent inflammatory environment and abnormal macrophage activation are characteristics of chronic diabetic wounds. Here, we attempted to characterize the differences in macrophage activation and temporal variations in cytokine expression in diabetic and non-diabetic wounds, with a focus on interleukin (IL)-6 mRNA expression and the p38 MAPK and PI3K/Akt signaling pathways. Cutaneous wound closure, CD68- and arginase-1 (Arg-1)-expressing macrophages, and cytokine mRNA expression were examined in non-diabetic and streptozotocin-induced type 1 diabetic mice at different time points after injury. The effect of IL-6 on p38 MAPK and Akt phosphorylation was investigated, and an in vitro scratch assay was performed to determine the role of IL-6 in primary skin fibroblast migration. Before injury, mRNA expression levels of the inflammatory markers iNOS, IL-6, and TNF-α were higher in diabetic mice; however, IL-6 expression was significantly lower 6 h post injury in diabetic wounds than that in non-diabetic wounds. Non-diabetic wounds exhibited increased p38 MAPK and Akt phosphorylation; however, no such increase was found in diabetic wounds. In fibroblasts from non-diabetic mice, IL-6 increased the phosphorylation of p38 MAPK and levels of its downstream factor CREB, and also significantly increased Akt phosphorylation and levels of its upstream factor P13K. These effects of IL-6 were not detected in fibroblasts derived from the diabetic mice. In scratch assays, IL-6 stimulated the migration of primary cultured skin fibroblasts from the non-diabetic mice, and the inhibition of p38 MAPK was found to markedly suppress IL-6–stimulated fibroblast migration. These findings underscore the critical differences between diabetic and non-diabetic wounds in terms of macrophage activation, cytokine mRNA expression profile, and involvement of the IL-6-stimulated p38 MAPK–Akt signaling pathway. Aberrant macrophage activation and abnormalities in the cytokine mRNA expression profile during different phases of wound healing should be addressed when designing effective therapeutic modalities for refractory diabetic wounds.
Highlights
2.8% of the world population is reported to be affected by diabetes, and approximately 15% of patients with diabetes have impaired cutaneous wound healing, which poses a serious risk of limb amputation and compromised quality of life [1, 2]
There were more CD68-positive macrophages in diabetic wounds than in non-diabetic wounds at the corresponding time points (Fig 2A), indicating that macrophages were present in both groups, there was a higher abundance of macrophages in diabetic wound skin
This study shows that the macrophage polarization status and expression of IL-6 significantly differ between non-diabetic and diabetic mice during pre-injury and in the early phase of wound healing
Summary
2.8% of the world population is reported to be affected by diabetes, and approximately 15% of patients with diabetes have impaired cutaneous wound healing, which poses a serious risk of limb amputation and compromised quality of life [1, 2]. A critical issue in non-healing diabetic wounds is a prolonged phase of inflammation and neutrophil infiltration, characterized by an abundance of pro-inflammatory macrophages, cytokines, and proteases. Macrophages are key modulators of host defense, wound healing, and immune regulation [3]. They are involved in distinct immune functions such as inflammation and tissue repair, and are classified into two distinct phenotypes: classically activated macrophages (M1) and alternatively activated macrophages (M2). Identifying the factors associated with macrophage dysfunction and cytokine dysregulation is crucial for preventing wounds from becoming arrested at the inflammatory stage, as well as for promoting the healing of diabetic wounds [11, 18, 19]
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