IL-10 Overexpression Decreases Inflammatory Mediators and Promotes Regenerative Healing in an Adult Model of Scar Formation

Abstract

Adult wound healing is characterized by an exuberant inflammatory response and scar formation. In contrast, scarless fetal wound healing has diminished inflammation, a lack of fibroplasia, and restoration of normal architecture. We have previously shown that fetal wounds produce less inflammatory cytokines, and the absence of IL-10, an anti-inflammatory cytokine, results in fetal scar formation. We hypothesized that increased IL-10 would decrease inflammation and create an environment conducive for regenerative healing in the adult. To test this hypothesis, a lentiviral vector expressing IL-10 and green fluorescent protein (GFP) (Lenti-IL-10) or GFP alone (Lenti-GFP) was injected at the wound site 48 hours before wounding. We found that both Lenti-IL-10 and Lenti-GFP were expressed in the wounds at 1 and 3 days post wounding. At 3 days, Lenti-IL-10-treated wounds demonstrated decreased inflammation and decreased quantities of all proinflammatory mediators analyzed with statistically different levels of IL-6, monocyte chemoattractant protein-1, and heat-shock protein 47. At 3 weeks, Lenti-GFP wounds demonstrated scar formation. In contrast, wounds injected with Lenti-IL-10 demonstrated decreased inflammation, a lack of abnormal collagen deposition, and restoration of normal dermal architecture. We conclude that lentivirus-mediated overexpression of IL-10 decreases the inflammatory response to injury, creating an environment conducive for regenerative adult wound healing.

Activity of mesenchymal stem cells in therapies for chronic skin wound healing

“…86,87 The upregulation of IL-10 in the wound by MSCs also has a multitude of effects on general scar formation, including downregulation of IL-6 and IL-8 to reduce collagen production in the wound 88 and inhibition of neutrophil invasion and macrophage activity to suppress ROS generation, 89 all leading to support of regenerative healing in recent experimental scar formation models. 90 ROS generation is also affected by nitric oxide secreted by MSCs, acting as a scavenger to prevent the fibrotic activity of the oxygen radicals. 91,92 Though these anti-inflammatory mechanisms are part of normal MSC function following homing to acute wound sites, the hyperinflammatory environment of a chronic wound makes the MSC ability to modulate excessive inflammation and reduce excessive scarring critical.…”

Oral or topical administration of L-arginine changes the expression of TGF and iNOS and results in early wounds healing

“…The results presented by the authors suggested that the IL-10 overexpression acts providing an environment supportive of a regenerative healing process that is characteristic of scarless wound healing 28 . However, despite the accelerated wound closure showed by Eming et al 29 in IL-10 deficient mice, the mechanical strength of wounds in IL-10-deficient mice is reduced,…”

“…It is interesting to notice that when mice were topically treated with dispersion of L-arginine at 40%, there was an increase in the IL-10 expression and in this same group of animals it was observed an increased collagen deposition. Since the administration of 40% L-arginine improved the expression of iNOS, the increased expression of IL-10 could be a compensation mechanism to control the inflammatory process, but it also could has acted as a mechanism to acquire a more organized collagen deposition, as occurred in the Peranteau et al 28 work. This, IL-10 expression control it is another rote to be investigated in the relation of L-arginine administration and collagen deposition.…”

“…In Peranteau et al 28 study, overexpression of IL-10 resulted in a decreased inflammatory infiltrate and a more organized collagen deposition. It is interesting to notice that when mice were topically treated with dispersion of L-arginine at 40%, there was an increase in the IL-10 expression and in this same group of animals it was observed an increased collagen deposition.…”

“…It was observed a significant increase in TGF-β levels in tissues of animals treated with L-arginine, either orally or topically, compared to those of control animals, and it was also observed that in topical treatment there was a higher expression of TGF-β than in the tissues of animals orally treated. It is tempting to speculate that the stimulation of macrophages with L-arginine leads to the production of TGF-β, Peranteau et al 28 investigated if IL-10 overexpression could decrease inflammation and create an environment conducive to scarless wound healing in adults. The authors concluded that this was an approach to be taken with caution, since wound healing process is composed by a serie of tightly regulated events whose attempt manipulation may result in unintended consequences.…”