MAdCAM-1 mediates retinal neuron degeneration in experimental colitis through recruiting gut-homing CD4+ T cells
MAdCAM-1 mediates retinal neuron degeneration in experimental colitis through recruiting gut-homing CD4+ T cells
复制标题
MAdCAM-1 通过招募肠道归巢 CD4 T 细胞介导实验性结肠炎中的视网膜神经元变性
DOI：
10.1038/s41385-020-0282-x
复制
发表时间：
2020-03-16
影响因子：
8
通讯作者：
Lu, Fang
中科院分区：
文献类型：
--
作者：
Peng, Kun;Xiao, Jie;Lu, Fang
肠外表现（EIMs）的眼睛被发现在IBD患者，但潜在的发病机制仍然未知。为了研究IBD相关视网膜功能障碍的发病机制，通过口服葡聚糖硫酸钠（DSS）诱导小鼠慢性结肠炎。采用视网膜电图（ERG）评价视网膜功能。免疫组化分析视网膜神经元变性。结肠炎小鼠表现出异常振幅的ERG a-，b-波和振荡电位（OP）。重要的是，我们观察到双极细胞和神经节细胞严重变性。相比之下，外视网膜神经元（主要是感光细胞）受到结肠炎的轻度影响。此外，在结肠炎期间视网膜炎症反应显著上调，包括小胶质细胞活化、淋巴细胞浸润和细胞因子/趋化因子产生。值得注意的是，粘膜地址素细胞粘附分子1（MAdCAM-1）在视网膜微血管，特别是浅表和深丛中上调，并招募肠道归巢CD 4 +T细胞与双极细胞和神经节细胞在结肠炎期间共定位。预期，体内CD 4 +T细胞的耗竭或MAdCAM-1的阻断极大地减轻了结肠炎诱导的视网膜炎症反应和神经元变性。因此，我们的数据为IBD相关视网膜功能障碍的发病机制提供了新的见解，并且直接针对MAdCAM-1的靶向免疫治疗可能为IBD的眼EIM的管理提供新的方法。
Extra-intestinal manifestations (EIMs) of the eyes are found in IBD patients, but the underlying pathogenesis remains unknown. To investigate the pathogenesis of IBD-associated retinal dysfunction, chronic colitis was induced in mice by oral administration of dextran sodium sulfate (DSS). Electroretinography (ERG) was performed to evaluate retinal function. Retinal neuron degeneration was analyzed by immunohistochemistry. Colitic mice displayed aberrant amplitudes of ERG a-, b-wave and oscillatory potentials (OP). Importantly, we observed severe degeneration of bipolar and ganglion cells. In contrast, outer retinal neurons (mainly photoreceptor cells) are mildly affected by colitis. Moreover, retinal inflammatory responses were significantly upregulated during colitis, including microglia activation, lymphocyte infiltration and cytokine/chemokine production. Notably, mucosal addressin cell adhesion molecule 1 (MAdCAM-1) was upregulated in retinal microvessels, especially the superficial and deep plexuses, and recruited gut-homing CD4+T cells to be co-localized with bipolar and ganglion cells during colitis. Expectedly, in vivo depletion of CD4+T cells or blockade of MAdCAM-1 greatly alleviated colitis-induced retinal inflammatory responses and neuron degeneration. Therefore, our data provide novel insight into the pathogenesis of IBD-associated retinal dysfunction, and targeted immune therapy directly against MAdCAM-1 might provide a novel approach in the management of eye EIM of IBD.