The expression of NKG2D ligand is induced in the cutaneous ischemia-reperfusion injury and mitigates pressure ulcer via NKG2D-NKG2D ligand interaction

Abstract

Abstract NKG2D is an activating receptor on NK cells, NKT cells, and several types of T-cells. The ligands for NKG2D are expressed on distressed cells, and NKG2D-NKG2D ligand interaction plays a major role in the surveillance against tumors and viral infection. Several studies have reported the physiological role of NKG2D-positive cells, such as NK cells, iNKT cells, and dendritic epidermal T-cells (DETCs) in skin tissue repair and wound healing. It has been proposed that a major etiology of pressure ulcers is reperfusion injury following ischemia, though the role of NKG2D and its ligands in the process remains to be clarified. Here we report the involvement of NKG2D-NKG2D ligand interaction in the cutaneous ischemia-reperfusion (I-R) injury. The wound size of cutaneous I-R injury was expanded in NKG2D-deficient mice, compared with wild-type and TCRδ knock-out mice. Histopathological evaluation revealed that the accumulation of macrophages and neutrophils was prominent at the periphery of the I-R injury site in NKG2D-deficient mice. The transcripts and the protein expression of murine NKG2D ligands, retinoic acid early inducible gene 1 (RAE-1), were detected in fibrocytes at the I-R injury site. The expression of RAE-1 transcripts was accelerated in primary fibroblasts cultures with sodium arsenite treatment. These results suggest that NKG2D ligand expression is induced by the oxidative stress at the I-R injury site. The pressure ulcer formation by the I-R injury is mitigated via NKG2D-NKG2D interaction. This process may be mediated by the influx of NKG2D-positive cells, which regulate the degree of acute inflammatory cells accumulation at the I-R injury site.