Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Bioengineering, Swanson School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Immunity. 2020 Nov 17;53(5):1050-1062.e5. doi: 10.1016/j.immuni.2020.10.013.
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）感染的角膜可发展为一种致盲性免疫炎症疾病，称为疱疹性基质角膜炎（HSK），其涉及感觉神经回缩和随后交感神经过度神经支配导致的角膜敏感性丧失。角膜中细胞因子 VEGF-A 的浓度增加与 HSK 的严重程度相关。在这里，我们使用 HSV-1 角膜感染的小鼠模型研究了 VEGF-A 对 HSK 潜在神经变化的影响。在 HSV-1 感染的角膜中，CD4 T 细胞和髓样细胞均产生致病水平的 VEGF-A，并且 CD4 细胞耗竭促进 HSK 角膜的感觉神经再支配。在体外，来自感染角膜的 VEGF-A 抑制感觉神经生长并促进交感神经生长。体内使用贝伐单抗中和 VEGF-A 可抑制交感神经支配，促进感觉神经再生，并缓解疾病。因此，VEGF-A 可以改变角膜内的感觉和交感神经景观，这对治疗致盲性角膜疾病具有重要意义。
