IL-13 From Murine Epidermal γδ T Cells Promotes Wound Healing by Inducing Arginase-1-Positive Hypodermal Macrophages...

Murine epidermal γδ T cells, known as dendritic epidermal T cells (DETCs), play critical roles in cutaneous wound healing by secreting chemokines, cytokines and growth factors. Although DETCs predominantly produce IL-13 early after activation, the specific role of DETC-derived IL-13 in wound repair remains unknown. Here, we show that periwound DETCs are the primary source of IL-13 at early wound sites (4 h after full-thickness skin wounding). The delayed wound closure in DETC-deficient Tcrd^-/- mice was restored by the local application of IL-13 immediately after wounding. Previous studies have demonstrated that macrophages infiltrating the wound granulation tissue undergo a phenotypic shift from iNOS-positive, proinflammatory type to arginase-1-positive, anti-inflammatory type during the late inflammatory phase (3-5 days post injury). At 24 h post wounding, however, most macrophages infiltrating the periwound hypodermis expressed arginase-1. In Tcrd^-/- mice, both the number of macrophages in the periwound hypodermis and their arginase-1 expression were significantly reduced. Local IL-13 administration restored arginase-1 expression in the hypodermal macrophages without altering their overall number in Tcrd^-/- mice. These results indicate that IL-13 rapidly produced by DETCs upon skin injury plays a critical role in wound healing by inducing arginase-1-positive macrophages in the periwound hypodermis during the early inflammatory phase.