Neutrophil pyroptosis regulates corneal wound healing and post-injury neovascularisation

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2024-11-04 DOI:10.1002/ctm2.1762

Peng Chen, Zhentao Zhang, Lilian Sakai, Yanping Xu, Shanzhi Wang, Kyung Eun Lee, Bingchuan Geng, Jongsoo Kim, Bao Zhao, Qiang Wang, Haitao Wen, Heather L. Chandler, Hua Zhu

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引用次数: 0

Abstract

Rationale

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.

Objective

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.

Methods and results

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.

Conclusion

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.

Key points

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.

Abstract Image

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中性粒细胞增殖调节角膜伤口愈合和损伤后新生血管形成。

理由：角膜是一种独特的结构，它通过保持无血管状态来保持其清晰度。角膜损伤可导致新生血管形成（CNV）和纤维化，是全球第三大常见致盲原因：角膜损伤会引起免疫细胞浸润，从而启动修复过程。然而，众所周知，免疫细胞持续浸润引起的炎症是有害的，会延迟愈合过程。本研究旨在了解中性粒细胞和上皮细胞串联在损伤后 CNV 中的潜在作用：Western印迹和免疫染色分析表明，中性粒细胞浸润角膜并在急性碱损伤后发生热凋亡。体内研究表明，热凋亡的一个关键效应因子 Gasdermin D (GsdmD) 的基因消减增强了角膜的再上皮化并抑制了损伤后的 CNV。体外共培养实验显示，嗜热中性粒细胞释放的白细胞介素-1β（IL-1β）抑制了小鼠角膜上皮细胞的迁移。实时 RT-PCR 和免疫染色检测发现，Wnt5a 和可溶性 fms 样酪氨酸激酶-1（sflt-1）这两种因子在新愈合的上皮细胞中高度表达。在活体小鼠角膜损伤模型中，骨髓移植、抗体介导的中性粒细胞耗竭和药物抑制热蛋白沉积可促进角膜伤口愈合并抑制 CNV：综上所述，我们的研究揭示了中性粒细胞/上皮细胞串联和中性粒细胞热凋亡在角膜损伤反应中的重要性。抑制中性粒细胞增殖可作为一种潜在的治疗方法，在无 CNV 的情况下促进角膜愈合：要点：中性粒细胞的热凋亡会延迟角膜损伤后的再上皮化，受损的再上皮化会促进损伤后角膜新生血管的形成。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.