DNase I Improves Corneal Epithelial and Nerve Regeneration in Diabetic Mice

Abstract

Background: Neutrophils aggregation, usually in the form of neutrophils extracellular traps (NETs), contributes to the delayed wound healing in diabetic condition. DNase I plays a vital role in NETs clearance, while the function and mechanism of DNase I on diabetes-related corneal wound healing is still remain unclear. Methods: Intraperitoneal streptozocin injection was used to induce type 1 diabetic mouse models, and 1mg/ml DNase I or PAD4 inhibitor (Cl-amidine) topical administration were used as treatments for tissue regeneration after corneal epithelial removal. Corneal epithelial defects, inflammatory response, regeneration related signaling pathways, oxidative stress, corneal nerve innervation and sensation were examined and quantized during the corneal epithelial and nerve regeneration both in diabetic and normal mice. Findings: Topical DNase I or Cl-amidine administration improved the corneal wound healing rate in diabetic mice. Meanwhile, DNase I application significantly improved inflammation resolution, reactivated epithelial regeneration-related signaling pathways, and attenuated the accumulation of reactive oxygen species (ROS). Moreover, DNase I application also prominently promoted corneal nerve regeneration, and restored the impaired corneal sensitivity in diabetic mice. Interpretation: DNase I promoted corneal epithelial wound healing and the restoration of mechanical sensation in diabetic mice, thereby topical application of DNase I may serve as a novel therapy for the treatment of delayed corneal wound healing in diabetic condition. Funding Statement: This work was partially funded by National Natural Foundation of China (81770904, 81800805, 81570820), Shandong Medical and Health Science Technology Development Project (2018WS233), Shandong Academy of Medical Sciences Technology Project (2018-21), Qingjun Zhou is partially supported by the Taishan Scholar Program (20150215, 20161059) and the Innovation Project of Shandong Academy of Medical Sciences. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All animal experiments were conducted with the approval of the Ethics Committee of Shandong Eye Institute according to the Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research.