Abstract
Sirtuins (SIRT1-7) are NAD-dependent proteins with the enzymatic activity of deacetylases and ADP ribosyltransferases. SIRT1 is the proto member of the proteins in the mammalian sirtuin family and plays multiple roles in aging and disease. Using mice with epidermis-specific SIRT1 deletion, we show that SIRT1 is required for efficient wound healing. SIRT1 deficiency in the epidermis inhibited the regeneration of both the epidermis and the dermal stroma. SIRT1 loss altered the production of many cytokines, inhibited the recruitment of macrophages, neutrophils, and mast cells, the recruitment and activation of fibroblasts, and angiogenesis in the granulation tissue. In keratinocytes, SIRT1 knockdown inhibited EMT, cell migration, and TGF-β signaling. For the first time, using skin-specific mouse model, we demonstrate that epidermal SIRT1 plays a crucial role in wound repair. These findings are novel in understanding how wound healing is regulated. Our findings provide in vivo and in vitro evidence that SIRT1 in the epidermis regulates cell migration, redox response, inflammation, epidermis re-epithelialization, granulation formation, and proper wound healing in mice.
Highlights
Sirtuins (SIRT1-7) are NAD-dependent proteins with the enzymatic activity of deacetylases and ADP ribosyltransferases[1,2,3,4,5]
Using mice with epidermis-specific SIRT1 deletion, we show that SIRT1 is required for efficient wound healing
To determine the role of SIRT1 in skin wound healing, we first assessed the difference in wound repair between wild-type (WT) mice and mice with a SIRT1 deletion in their epidermis (SIRT1 cKO, conditional knockout), using full-thickness excisional wounds introduced to the dorsal skin of mice
Summary
Sirtuins (SIRT1-7) are NAD-dependent proteins with the enzymatic activity of deacetylases and ADP ribosyltransferases[1,2,3,4,5]. The process of wound re-epithelialization requires efficient coordination of multiple events, including the formation of a provisional wound bed matrix, the proliferation and migration of keratinocytes into the wound, the differentiation of new epithelium into stratified epidermis, and the activation and migration of fibroblasts into the provisional matrix. It remains poorly understood how these processes are coordinated and regulated at the molecular, cellular and organismal levels. SIRT1 regulates epidermal re-epithelialization and generation of dermal granulation tissue as well as keratinocyte migration, cytokine expression, TGF-β signaling, and oxidative stress
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