Involvement of DPP IV/CD26 in cutaneous wound healing process in mice

Abstract

Dipeptidyl peptidase IV (DPP IV/CD26) is a widely distributed multifunctional protein that plays a significant role in different physiological as well as pathological processes having a broad spectrum of bioactive substrates and immunomodulative properties. It has potential influence on different processes crucial for wound healing, including cell adhesion, migration, apoptosis, and extracellular matrix degradation. However, despite its known enzymatic and immunomodulative functions, limited data characterize the role of DPP IV/CD26 in cutaneous wound healing mechanisms. The aim of this study was to investigate the process of wound healing in conditions of CD26 deficiency in order to obtain better insights on the role of DPP IV/CD26 in cutaneous regeneration. Experimental wounds were made on the dorsal part of CD26 deficient (CD26 ) and wild-type mice (C57BL/6). The process of cutaneous wound healing was monitored on defined time schedule postwounding by macroscopic, microscopic, and biochemical analyses. Obtained results revealed a better rate of wound closure, revascularization and cell proliferation in CD26 mice, with enhanced local expression of hypoxia-inducible factor 1α and vascular endothelial growth factor. CD26 deficiency induced prompt macrophage recruitment at the site of skin damage but did not influence mobilization of T-cells in comparison with wild-type mice. CD26 mice have significantly higher values of IP-10 in serum and control skins compared with wild-type mice but values in wounds did not differ significantly on days 2, 4, and 7 of wound healing. DPP IV/CD26 activity was found to be decreased 4 days postwounding in serum and 2, 4, and 7 days postwounding in wounds of wild-type animals compared with control skins. These findings contribute to better understanding of wound healing mechanisms and could give a support in finding new therapeutic approaches for wound healing and tissue regeneration.

The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs

“…Its expression has been shown to vary during different phases of the wound repair process and, more specifically, the presence of high levels of DPP4 in diabetic wounds in mice is indicative of the persistence of an inflammatory status that impairs the healing process. Accordingly, DPP4 knockout mice display accelerated wound closure [95] and inhibition of DPP4 activity results in enhanced re-epithelialization of impaired wound healing in diabetic animals [96]. This finds support also in studies carried out in keratinocytes cultured in vitro where expression of DPP4 is increased when a wound is mechanically produced in the monolayer and inhibition of both expression and activity of the enzyme results in improved wound repair [97].…”

DPP-4 Inhibitors Improve Diabetic Wound Healing via Direct and Indirect Promotion of Epithelial-Mesenchymal Transition and Reduction of Scarring

“…This enzyme is widely expressed by many types of cells, such as normal epithelial cells, tumor cells, and immune cells, and displays diverse biological functions (18)(19)(20). DPP-4 can take part in regulation of tissue regeneration by affecting angiogenesis, cell survival, and proliferation through its substrates, such as GLP-1 and interferon-g-inducible protein 10 (IP-10) (21, 22). Its immunomodulatory function has also been identified to contribute to tissue repair by regulating lymphocyte T-cell activation and monocyte/macrophage recruitment (22,23).…”

Wound Healing Process, Diabetes and Implications of Dipeptidyl Peptidase IV (DPP IV/CD26)

“…Animal studies in diabetic mice revealed increased DPP IV/CD26 levels in the presence of enhanced wound inflammatory conditions [42]. Our research group also demonstrated an important role of DPP IV/CD26 in the process of wound healing [43]. We showed an increase in epithelium thickness, corium connective tissue, and extracellular matrix was demonstrated in CD26 deficient mice during wound healing.…”