Weakened IL-15 Production and Impaired mTOR Activation Alter Dendritic Epidermal T Cell Homeostasis in Diabetic Mice

Abstract

Diabetes is associated with impaired wound healing, which may be caused primarily by a deficiency in dendritic epidermal T cells (DETCs). In the epidermis, IL-15, IGF-1, and mTOR are known to regulate the maintenance of DETCs; however, it is unclear how these molecules may intersect to regulate DETC homeostasis in diabetes. Here, we show that the reduction of DETCs in the epidermis of diabetic mice is caused by altered homeostasis mediated by a reduction in IL-15 levels. Both impaired mTOR activation and reduction of IL-15 in the epidermis play important roles in DETC homeostasis. Moreover, IGF-1 drives keratinocytes to produce IL-15. The activation of IL-15 is dependent on mTOR, and conversely, mTOR regulates IGF-1 production in DETC, in a classic feedback regulatory loop. Our data suggest that in the setting of diabetes, reduced IGF-1, impaired mTOR pathway activation and reduced IL-15 in the epidermis function coordinately to promote altered DETC homeostasis and delayed skin wound closure.

IL-15 Enhances Activation and IGF-1 Production of Dendritic Epidermal T Cells to Promote Wound Healing in Diabetic Mice

“…Impaired mTOR signaling has been exhibited in diabetic epidermis. Others and our previous studies showed that mTOR signaling was deeply involved in regulating IGF-1 production in epidermis and DETCs ( 8 ). Now, we showed that rapamycin (an inhibitor of mTOR signaling) notably inhibited IGF-1 production in DETCs, which were freshly isolated from wound area by MACS, in the presence of rIL-15 plus anti-CD3 stimulation in vitro (Figure 4 B), suggesting that mTOR was involved in IL-15-mediated upregulation of IGF-1 production from DETCs.…”

“…IL-15 has been reported to play crucial roles in development and homeostasis of DETCs ( 19 , 32 ). Recently, we showed that reduction of epidermal IL-15 contributed to the altered homeostasis of DETCs in STZ-induced diabetic mice ( 8 ). In this study, we further revealed that impaired epidermal IL-15 production was a critical reason for insufficient activation and reduced IGF-1 production of DETCs in diabetic animals.…”

“…The altered homeostasis and dysfunctions of DETCs contribute to impaired diabetic wound healing ( 6 , 7 ). Further, a notable reduction of epidermal IGF-1 production, which is majorly secreted by DETCs, has been reported in streptozotocin (STZ)-induced diabetic animals ( 8 ). Moreover, addition of rIGF-1 onto wound bed significantly improves defects of diabetic wound healing ( 9 – 12 ).…”

“…IL-15 is required for the development and homeostasis of DETCs in the epidermis ( 18 – 20 ). Recently, reduced epidermal IL-15 production has been shown to participate in altering DETC homeostasis of STZ-induced diabetic animals ( 8 ). However, the precise roles of IL-15 in the abnormal activation of DETCs and delayed skin wound closure in diabetic animals have not yet been clarified.…”

“…Keratinocytes are a major source of IL-15 in the epidermis ( 18 ). IGF-1 directly stimulates keratinocytes to produce IL-15 partly through an mTOR-dependent pathway ( 8 ). Furthermore, the productions of IGF-1 and IL-15 in the epidermis exhibit similar kinetics in STZ-induced diabetic mice and rapamycin-treated non-diabetic animals ( 25 ), suggesting that keratinocyte-derived IL-15 and DETC-derived IGF-1 closely correlated with each other in epidermis.…”