Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
College of Pharmacy and Health Sciences, St. John's University, Queens, New York, USA.
Clin Transl Med. 2024 Nov;14(11):e1762. doi: 10.1002/ctm2.1762.
The cornea is a unique structure that maintains its clarity by remaining avascular. Corneal injuries can lead to neovascularisation (CNV) and fibrosis and are the third most common cause of blindness worldwide.
Corneal injuries induce an immune cell infiltration to initiate reparative processes. However, inflammation caused by sustained immune cell infiltration is known to be detrimental and can delay the healing process. This study was designed to understand the potential role of neutrophil and epithelial cell crosstalk in post-injury CNV.
Western blotting and immunostaining assays demonstrated that neutrophils infiltrated corneas and underwent pyroptosis following acute alkali injury. In vivo studies showed that genetic ablation of Gasdermin D (GsdmD), a key effector of pyroptosis, enhanced corneal re-epithelialisation and suppressed post-injury CNV. In vitro co-culture experiments revealed that interleukin-1β (IL-1β) was released from pyroptotic neutrophils which suppressed migration of murine corneal epithelial cells. Real-time RT-PCR and immunostaining assays identified two factors, Wnt5a and soluble fms-like tyrosine kinase-1 (sflt-1), highly expressed in newly healed epithelial cells. sflt-1 is known to promote corneal avascularity. Bone marrow transplantation, antibody mediated neutrophil depletion, and pharmacological inhibition of pyroptosis promoted corneal wound healing and inhibited CNV in an in vivo murine corneal injury model.
Taken together, our study reveals the importance of neutrophil/epithelium crosstalk and neutrophil pyroptosis in response to corneal injuries. Inhibition of neutrophil pyroptosis may serve as a potential treatment to promote corneal healing without CNV.
Neutrophil pyroptosis delays re-epithelialization after corneal injury Compromised re-epithelialization promotes corneal neovascularization after injury Inhibition of post-injury pyroptosis could be an effective therapy to promote corneal wound healing.
角膜是一种独特的结构，通过保持无血管状态来保持其透明度。角膜损伤可导致新生血管形成（CNV）和纤维化，是全球第三大致盲原因。
角膜损伤会引发免疫细胞浸润，启动修复过程。然而，持续的免疫细胞浸润引起的炎症已知是有害的，并可能延迟愈合过程。本研究旨在了解中性粒细胞和上皮细胞相互作用在损伤后 CNV 中的潜在作用。
Western blot 和免疫染色检测表明，中性粒细胞在急性碱损伤后浸润角膜并发生细胞焦亡。体内研究表明，细胞焦亡的关键效应因子 Gasdermin D（GsdmD）的基因缺失增强了角膜再上皮化并抑制了损伤后 CNV。体外共培养实验表明，细胞焦亡的中性粒细胞释放白细胞介素-1β（IL-1β），抑制了小鼠角膜上皮细胞的迁移。实时 RT-PCR 和免疫染色检测鉴定出两种在新愈合的上皮细胞中高表达的因子，Wnt5a 和可溶性 fms 样酪氨酸激酶-1（sflt-1）。sflt-1 已知可促进角膜无血管化。骨髓移植、抗体介导的中性粒细胞耗竭和细胞焦亡的药理学抑制促进了体内小鼠角膜损伤模型中的角膜伤口愈合并抑制了 CNV。
综上所述，我们的研究揭示了中性粒细胞/上皮细胞相互作用和中性粒细胞细胞焦亡在角膜损伤反应中的重要性。抑制中性粒细胞细胞焦亡可能成为促进角膜愈合而不发生 CNV 的潜在治疗方法。
中性粒细胞细胞焦亡延迟角膜损伤后的再上皮化受损的再上皮化促进损伤后的角膜新生血管形成抑制损伤后细胞焦亡可能是促进角膜伤口愈合的有效治疗方法。
