Departments of Ophthalmology, The University of Oklahoma Health Sciences Center (OUHSC), 608 Stanton L. Young Blvd., DMEI PA415, Oklahoma City, OK. 73104, USA.
Microbiology and Immunology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
Sci Rep. 2021 May 13;11(1):10247. doi: 10.1038/s41598-021-89818-9.
Corneal transparency is an essential characteristic necessary for normal vision. In response to microbial infection, the integrity of the cornea can become compromised as a result of the inflammatory response and the ensuing tissue pathology including neovascularization (NV) and collagen lamellae destruction. We have previously found complement activation contributes to cornea pathology-specifically, denervation in response to HSV-1 infection. Therefore, we investigated whether the complement system also played a role in HSV-1-mediated neovascularization. Using wild type (WT) and complement component 3 deficient (C3 KO) mice infected with HSV-1, we found corneal NV was accelerated associated with an increase in inflammatory monocytes (CD11bCCR2CD115Ly6GLy6C), macrophages (CD11bCCR2CD115Ly6GLy6C) and a subpopulation of granulocytes/neutrophils (CD11bCCR2CD115Ly6GLy6C). There were also increases in select pro-inflammatory and pro-angiogenic factors including IL-1α, matrix metalloproteinases (MMP)-2, MMP-3, MMP-8, CXCL1, CCL2, and VEGF-A that coincided with increased inflammation, neovascularization, and corneal opacity in the C3 KO mice. The difference in inflammation between WT and C3 KO mice was not driven by changes in virus titer. However, viral antigen clearance was hindered in C3 KO mouse corneas suggesting the complement system has a dynamic regulatory role within the cornea once an inflammatory cascade is initiated by HSV-1.
角膜透明性是正常视力所必需的基本特征。为了应对微生物感染，角膜的完整性可能会因炎症反应以及随之而来的组织病理学改变而受损，包括新生血管形成（NV）和胶原板层破坏。我们之前发现补体激活会导致角膜病理学改变，特别是在单纯疱疹病毒 1 （HSV-1）感染时的去神经支配。因此，我们研究了补体系统是否也在 HSV-1 介导的新生血管形成中发挥作用。我们使用野生型（WT）和补体成分 3 缺陷（C3 KO）小鼠感染 HSV-1，发现角膜 NV 加速，同时炎症性单核细胞（CD11bCCR2CD115Ly6GLy6C）、巨噬细胞（CD11bCCR2CD115Ly6GLy6C）和粒细胞/中性粒细胞的一个亚群（CD11bCCR2CD115Ly6GLy6C）增加。还增加了一些选择的促炎和促血管生成因子，包括白细胞介素 1α（IL-1α）、基质金属蛋白酶（MMP）-2、MMP-3、MMP-8、趋化因子（CXCL1）、CCL2 和血管内皮生长因子 A（VEGF-A），这些因子的增加与 C3 KO 小鼠的炎症、新生血管形成和角膜混浊相一致。WT 和 C3 KO 小鼠之间的炎症差异不是由病毒滴度的变化驱动的。然而，在 C3 KO 小鼠的角膜中，病毒抗原的清除受到阻碍，这表明补体系统在 HSV-1 引发炎症级联反应后，在角膜中具有动态的调节作用。
