In This Issue of Diabetes

摘要

Diabetes is a recognized risk factor for impaired cutaneous wound healing, but less is known about its impact on mucosal wound repair. Data in this issue of Diabetes by Xu et al. (p. 243) suggest a complex role for Forkhead box 1 (Foxo1) in the link between diabetes and mucosal wound healing. Keratinocytes are epidermal cells whose motility and proliferation facilitate re-epithelialization, the process by which an intact epidermal barrier is re-established after injury. Regulatory cytokines associated with inflammation play an important role in this process because they affect the migration of keratinocytes to the site of a wound. In the newly published work, Foxo1 was removed from keratinocytes of Cre transgenic mice to determine the impact of this deletion on wound healing. Mice in four treatment groups-normoglycemic Foxo1 -control (NG control), normoglycemic Foxo1 -knockdown (NG knockdown), diabetic Foxo1 -control (diabetic control), and diabetic Foxo1 -knockdown (diabetic knockdown)-received small wounds to the tongue. On days 1 and 2 after wounding, tissue was harvested, wound size was quantified, and migration and proliferation of mucosal epithelial cells were estimated. The results showed that diabetic controls were slower to heal than normoglycemic controls: On day 1 of healing, wounds in the diabetic control mice were about 70% larger than their normoglycemic counterparts. Compared with normoglycemic mice, diabetic controls also exhibited significantly reduced epithelial cell proliferation and an 83% decrease in epithelial cell migration. Deletion of Foxo1 partly negated the unfavorable impact of diabetes, with diabetic knockdown mice showing a 98% improvement in cell proliferation and a 63% improvement in overall wound healing compared with diabetic controls. Surprisingly, after 1 day, wound healing was impeded in NG knockdown mice, whose wounds were 37% larger than matched controls. To understand the divergent impact of Foxo1 deletion, human mucosal epithelial cells were cultured under high-glucose or standard conditions. These experiments focused on measures of CCL20 and IL-36γ, proinflammatory cytokines that are associated with the inhibition of epithelial cell migration. Under high-glucose conditions, Foxo1 promoted CCL20 and IL-36γ expression, while Foxo1 deletion prevented increases in both cytokines. By contrast, under normoglycemic conditions, Foxo1 stimulated transforming growth factor-β1 (TGF-β1), a growth factor that aids in the healing process. Taken together, these results contribute substantially to improved understanding of the mechanisms that underpin the role of Foxo1 in mucosal wound healing.