Tanno Hiromasa, Kawakami Kazuyoshi, Kanno Emi, Suzuki Aiko, Takagi Naoyuki, Yamamoto Hideki, Ishii Keiko, Imai Yoshimichi, Maruyama Ryoko, Tachi Masahiro
Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Japan.
Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Wound Repair Regen. 2017 Sep;25(5):805-815. doi: 10.1111/wrr.12588. Epub 2017 Dec 8.
The wound-healing process consists of the inflammation, proliferation, and remodeling phases. In chronic wounds, the inflammation phase is prolonged with persistent neutrophil infiltration. The inflammatory response is critically regulated by cytokines and chemokines that are secreted from various immune cells. Recently, we showed that skin wound healing was delayed and the healing process was impaired under conditions lacking invariant natural killer T (iNKT) cells, an innate immune lymphocyte with potent immuno-regulatory activity. In the present study, we investigated the effect of iNKT cell deficiency on the neutrophilic inflammatory response during the wound healing process. Neutrophil infiltration was prolonged in wound tissue in mice genetically lacking iNKT cells (Jα18KO mice) than in wild-type (WT) control mice on days 1 and 3 after wounding. MIP-2, KC, and IL-17A were produced at a significantly higher level in Jα18KO mice than in WT mice. In addition, neutrophil apoptosis was significantly reduced in the wound tissue in Jα18KO mice than in WT mice. Treatment with anti-IL-17A mAb, anti-Gr-1 mAb, or neutrophil elastase inhibitor reversed the impaired wound healing in Jα18KO mice. These results suggest that iNKT cells may promote the wound healing process through preventing the prolonged inflammatory response mediated by neutrophils.
伤口愈合过程包括炎症、增殖和重塑阶段。在慢性伤口中，炎症阶段会因持续的中性粒细胞浸润而延长。炎症反应受到各种免疫细胞分泌的细胞因子和趋化因子的严格调控。最近，我们发现，在缺乏不变自然杀伤T细胞（iNKT细胞）的情况下，皮肤伤口愈合会延迟，愈合过程会受到损害，iNKT细胞是一种具有强大免疫调节活性的先天性免疫淋巴细胞。在本研究中，我们调查了iNKT细胞缺陷对伤口愈合过程中嗜中性粒细胞炎症反应的影响。在受伤后第1天和第3天，基因敲除iNKT细胞的小鼠（Jα18KO小鼠）伤口组织中的中性粒细胞浸润比野生型（WT）对照小鼠持续时间更长。Jα18KO小鼠体内MIP-2、KC和IL-17A的产生水平显著高于WT小鼠。此外，Jα18KO小鼠伤口组织中的中性粒细胞凋亡明显低于WT小鼠。用抗IL-17A单克隆抗体、抗Gr-1单克隆抗体或中性粒细胞弹性蛋白酶抑制剂治疗可逆转Jα18KO小鼠受损的伤口愈合。这些结果表明，iNKT细胞可能通过防止中性粒细胞介导的炎症反应延长来促进伤口愈合过程。
