Department of Dermatology, Changhai Hospital, Naval Medical University, Shanghai, China.
Department of Dermatology, Henry Ford Health System, Detroit, Michigan, USA.
Adv Wound Care (New Rochelle). 2022 Jan;11(1):19-27. doi: 10.1089/wound.2020.1165. Epub 2021 Jul 2.
MiRNAs are important regulators of inflammation and wound healing. However, the mechanisms through which miRNAs regulate wound healing under normal and diabetic conditions are poorly understood. We aimed to determine the effects of miR-146a on the pathogenesis of wound healing in normal and streptozotocin (STZ)-induced diabetic mice. Wild-type (WT) and miR-146a knockout (KO) mice were induced to develop diabetes with STZ. Next, skin and corneal wounds were produced and measured. Percent wound closure and histology were evaluated. Inflammation at wound sites was analyzed using flow cytometry, reverse-transcription PCR, and western blot. Healing of wounded skin was significantly delayed in miR-146a KO compared with WT mice. However, corneal epithelial wound healing did not differ significantly in the mice with normal blood glucose, whereas corneal and skin wound healing was significantly delayed in KO mice with diabetes. Neutrophil infiltration increased in skin wounds of KO compared with normal mice. The potential mechanisms were associated with dysregulated interleukin 1β, tumor necrosis factor alpha (TNF-α), IRAK1 (interleukin-1 receptor-associated kinase 1), TRAF6 (TNF receptor-associated factor 6), and nuclear factor kappa B (NF-κB) signaling induced by miR-146a KO. Skin wound healing was delayed in miR-146a KO mice and enhanced inflammatory responses were mediated by the NF-κB signaling pathway. Deficiency in miR-146a delayed skin wound healing by enhancing inflammatory responses in normal and diabetic mice. Therefore, miR-146a may be a potential target for modulation to accelerate skin wound healing.
miRNAs 是炎症和伤口愈合的重要调节因子。然而，miRNAs 在正常和糖尿病条件下调节伤口愈合的机制还知之甚少。我们旨在确定 miR-146a 对正常和链脲佐菌素（STZ）诱导的糖尿病小鼠伤口愈合发病机制的影响。野生型（WT）和 miR-146a 敲除（KO）小鼠用 STZ 诱导糖尿病。然后产生和测量皮肤和角膜伤口。评估伤口闭合百分比和组织学。使用流式细胞术、逆转录 PCR 和 Western blot 分析伤口部位的炎症。与 WT 小鼠相比，miR-146a KO 小鼠的皮肤伤口愈合明显延迟。然而，血糖正常的小鼠角膜上皮伤口愈合没有明显差异，而糖尿病 KO 小鼠的角膜和皮肤伤口愈合明显延迟。与正常小鼠相比，KO 小鼠皮肤伤口中的中性粒细胞浸润增加。潜在的机制与 miR-146a KO 引起的白细胞介素 1β、肿瘤坏死因子 α（TNF-α）、白细胞介素 1 受体相关激酶 1（IRAK1）、TNF 受体相关因子 6（TRAF6）和核因子 kappa B（NF-κB）信号转导失调有关。miR-146a KO 小鼠的皮肤伤口愈合延迟，NF-κB 信号通路介导的炎症反应增强。miR-146a 的缺乏通过增强正常和糖尿病小鼠的炎症反应延迟皮肤伤口愈合。因此，miR-146a 可能是加速皮肤伤口愈合的潜在调节靶点。
