Contribution of Invariant Natural Killer T Cells to Skin Wound Healing

Abstract

In the present study, we determined the contribution of invariant natural killer T (iNKT) cells to the skin wound healing process. In iNKT cell-deficient (Jα18KO) mice lacking iNKT cells, wound closure was significantly delayed compared with wild-type mice. Collagen deposition, expression of α-smooth muscle actin and CD31, and wound breaking strength were significantly attenuated in Jα18KO mice. The adoptive transfer of liver mononuclear cells from wild-type but not from Jα18KO or interferon (IFN)-γ gene-disrupted (IFN-γKO) mice resulted in the reversal of this impaired wound healing in Jα18KO mice. IFN-γ expression was induced in the wounded tissues, which was significantly decreased at 6, 12, and 24 hours, but increased on day 3 after wounding in Jα18KO mice. The main source of the late-phase IFN-γ production in Jα18KO mice were neutrophils rather than NK cells and T cells. Administration of α-galactosylceramide, an activator of iNKT cells, resulted in the acceleration of wound healing on day 3 in wild-type mice. This effect was not observed in IFN-γKO mice. These results indicate that iNKT cells play important roles in wound healing. The iNKT cell-induced IFN-γ production may regulate the wound healing process in the early phase.

Toll-Like Receptor Function in Acute Wounds

“…Resident immune cells in noninflamed dermis include dermal DCs, macrophages, and mast cells. An inflamed dermis may contain neutrophils, macrophages, eosinophils, and lymphocytes, including T, natural killer T (NKT), and B cells 3,16,17 Skin wound healing is a complicated pathophysiological process that consists of four overlapping phases: a hemostasis phase, characterized by fibrin clot formation and platelet activation/ aggregation; an inflammatory phase, characterized by neutrophil and macrophage infiltration; a proliferative phase, dominated by reepithelialization, collagen synthesis, and angiogenesis; and a remodeling phase, involving the resolution of inflammation, pruning of excessive blood vessels, and collagen maturation. 18,19 In this section, we will discuss TLR expression in skin resident and nonresident cells and their roles in wound healing (summarized in Table 2).…”

Invariant NKT cells promote skin wound healing by preventing a prolonged neutrophilic inflammatory response

“…A previous study reported that increased neutrophil accumulation in the liver was suppressed after α‐GalCer injection into IFN‐γ‐deficient mice . In our previous study, α‐GalCer‐treated mice exhibited enhanced IFN‐γ production in wound tissue . This finding suggests that the IFN‐γ secreted from iNKT cells may be involved in neutrophil accumulation.…”

“…In addition, previous studies reported that lack of IFN‐γ production led to enhanced IL‐17A production in mice infected with Mycobacterium bovine and in a mouse model of antigen‐induced arthritis . In our recent studies, IFN‐γ production was shown to be attenuated in wound tissue under iNKT cell–deficient conditions . Considered collectively, the reduction in IFN‐γ production may contribute to the prolonged neutrophil accumulation and attenuated wound healing observed in iNKT cell–deficient mice through an increase in IL‐17A production.…”

“…We have not examined how iNKT cells affect the development of chronic wounds, such as diabetic ulcers. However, we previously demonstrated that activation of iNKT cells by α‐GalCer promoted wound healing in addition to the attenuated neutrophilic responses. Clinical trials for a novel therapy with α‐GalCer are being conducted in patients with lung cancer and head and neck tumors .…”

“…iNKT cells are quickly activated by stimulation with α‐galactosylceramide (α‐GlaCer), a glycolipid antigen specific for these cells that was originally found in marine sponges as a novel anticancer agent, and the iNKT cells then produce a large amount of interferon (IFN)‐γ and interleukin (IL)‐4 . Our recent research showed that iNKT cell deficiency resulted in a delayed wound healing process, which was associated with reduced IFN‐γ production . However, interaction of iNKT cells with other immune cells, particularly as neutrophils, during the skin wound healing process remains to be fully clarified.…”