Diabetes‐impaired wound healing and altered macrophage activation: A possible pathophysiologic correlation

Abstract

Macrophages play a critical role in wound healing and can be activated to two distinctive phenotypes in vitro: classical macrophage activation (caM) and alternative macrophage activation (aaM). This study investigated whether the impaired cutaneous repair observed in streptozotocin-induced diabetic rats was associated with altered macrophage activation. Our results show that macrophage activation phenotypes could be observed in wound healing through double immunostaining. The caM macrophages appeared in the initial stage of wound healing, followed by aaM macrophages, which predominated in normal wounds. However, through examining markers associated with activation by immunoblotting and real-time polymerase chain reaction (PCR), diabetic wounds demonstrated insufficient caM in the early stage but excessive aaM in the later proliferative phase. Moreover, the macrophage activation markers were correlated with the instructive T helper cell type 1 (Th1)/Th2 cytokines in both groups. It was indicated that changed macrophage activation might contribute to impaired healing in diabetes wounds, and that strategies for reverting this abnormal activation could be useful for enhancing the wound healing process.

Interleukin-6 stimulates Akt and p38 MAPK phosphorylation and fibroblast migration in non-diabetic but not diabetic mice

“…Refractory diabetic wounds are characterized by a persistent inflammatory response, leading to impaired progression of the healing process [3, 11, 12, 16]. 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.…”

“…Macrophage depletion and/or aberrant activation are known to result in impaired wound healing [12, 16, 34]. In diabetic wounds, we noted significantly increased expression of the macrophage marker CD68 at almost all time points, ruling out a role for macrophage depletion–associated impairment in diabetic wound repair [35].…”

“…In non-diabetic wounds, the M1 phenotype appears in the initial stage of wound healing, followed by the M2 phenotype at later stages. Diabetic wounds, however, exhibit abnormal macrophage activation, showing insufficient M1 in the early stage and delayed activation of M2 [12, 13]. Macrophages are a major source of cytokines in wounds, and their dysfunction is known to be a factor in the pathogenesis of chronic wounds in diabetes [14–17].…”

Upregulation of Ski in Fibroblast is Implicated in the Peroxisome Proliferator- Activated Receptor d-Mediated Wound Healing

“…Skin wound repair is divided into three phases: inflammation, epithelialization and remodeling [36]. Keratinocytes, macrophages and dermal fibroblasts is critical for this repair process [37][38][39]. Previous studies have demonstrated that activation of PPARδ in keratinocytes increased resistance of the keratinocytes to the apoptotic signals released during wounding, allowing faster re-epithelialisation [23,35], and activation of PPARδ in infiltrated macrophages attenuates the inflammatory response [31,34,40], which also promotes repair.…”

Palatogenesis and cutaneous repair: A two‐headed coin

“…Some studies report faster epithelialization in mice lacking innate immune cells (Dovi et al, 2003; Cooper et al, 2005), others unchanged healing (Martin et al, 2003), while models lacking macrophages demonstrate delayed tissue repair (Goren et al, 2009; Mirza et al, 2009). However, it becomes evident that the disappearance of inflammatory cells is required for healing to proceed, and that the persistence and/or the dysfunction of innate immune cells leads to impaired healing as exemplified by chronic inflammation in diabetic foot ulcers and chronic wounds (Khanna et al, 2010; Pukstad et al, 2010; Miao et al, 2012). …”