Herpes simplex virus type 1 (HSV-1)-infected corneas can develop a blinding immunoinflammatory condition called herpes stromal keratitis (HSK), which involves the loss of corneal sensitivity due to retraction of sensory nerves and subsequent hyperinnervation with sympathetic nerves. Increased concentrations of the cytokine VEGF-A in the cornea are associated with HSK severity. Here, we examined the impact of VEGF-A on neurologic changes that underly HSK using a mouse model of HSV-1 corneal infection. Both CD4⁺ T cells and myeloid cells produced pathogenic levels of VEGF-A within HSV-1-infected corneas, and CD4⁺ cell depletion promoted reinnervation of HSK corneas with sensory nerves. In vitro, VEGF-A from infected corneas repressed sensory nerve growth and promoted sympathetic nerve growth. Neutralizing VEGF-A in vivo using bevacizumab inhibited sympathetic innervation, promoted sensory nerve regeneration, and alleviated disease. Thus, VEGF-A can shape the sensory and sympathetic nerve landscape within the cornea, with implications for the treatment of blinding corneal disease.

单纯疱疹病毒 1 型 (HSV-1) 感染的角膜会出现致盲性免疫炎症，称为疱疹性基质角膜炎 (HSK)，其涉及由于感觉神经收缩和随后的交感神经过度支配导致角膜敏感性丧失。角膜中细胞因子 VEGF-A 浓度的增加与 HSK 的严重程度有关。在这里，我们使用 HSV-1 角膜感染的小鼠模型检查了 VEGF-A 对 HSK 基础神经系统变化的影响。CD4 ⁺ T 细胞和骨髓细胞在 HSV-1 感染的角膜内产生致病性水平的 VEGF-A，CD4 ⁺细胞耗竭促进了 HSK 角膜与感觉神经的再支配。体外，来自受感染角膜的 VEGF-A 抑制感觉神经生长并促进交感神经生长。使用贝伐单抗在体内中和 VEGF-A可抑制交感神经支配、促进感觉神经再生并减轻疾病。因此，VEGF-A 可以塑造角膜内的感觉和交感神经景观，对治疗致盲性角膜疾病具有重要意义。