A Deficiency in the Cytokine TNFSF14/LIGHT Limits Inflammation and Remodeling in Murine Eosinophilic Esophagitis
A Deficiency in the Cytokine TNFSF14/LIGHT Limits Inflammation and Remodeling in Murine Eosinophilic Esophagitis
复制标题
DOI：
10.4049/jimmunol.2200326
复制
发表时间：
2022-12-15
影响因子：
4.4
通讯作者：
Croft, Michae
中科院分区：
文献类型：
--
作者：
Manresa, Mario C.;Miki, Haruka;Croft, Michae
嗜酸性食管炎(EoE)是一种慢性2型过敏性疾病，食道组织重塑是临床吞咽困难和狭窄的机制。IL-13被认为是疾病的主要驱动因素，但其他炎症因子，如干扰素和肿瘤坏死因子超家族成员，已被假设在疾病发病机制中发挥作用。我们最近发现，细胞因子TNFSF14/LIGHT在EoE患者的食道中表达上调，LIGH促进了食道成纤维细胞的炎症活动。然而，LIGH在体内对EoE发病机制的整体影响仍不清楚。我们研究了光缺乏对由屋尘螨变应原驱动的EoE小鼠模型的影响。室内尘螨慢性鼻腔攻击可促进野生型小鼠的食道嗜酸性粒细胞增多，并增加CD4+T细胞数量及IL-13和CCL11的产生。食道重塑表现为粘膜下胶原蛋白堆积、肌肉密度增加和成纤维细胞数量增多。Light-/-小鼠表现出正常的食道嗜酸性粒细胞增多，但CD4T细胞、IL-13表达、粘膜下胶原蛋白和肌肉密度降低，食道内成纤维细胞聚集减少。在体外，LIGH促进了人食道成纤维细胞的分裂，并选择性地增强了IL-13介导的炎症和纤维化基因亚集的表达。这些结果表明，光照影响了小鼠EoE的各种特征，影响了CD4T细胞的积聚、IL-13的产生、成纤维细胞的增殖和食道重塑。这些发现表明，据我们所知，光可能是治疗EoE的一个新的治疗靶点。免疫学杂志，2022,209：2341-2351。
Eosinophilic esophagitis (EoE) is a chronic type 2 allergic disease, with esophageal tissue remodeling as the mechanism behind clinical dysphagia and strictures. IL-13 is thought to be a central driver of disease, but other inflammatory factors, such as IFNs and TNF superfamily members, have been hypothesized to play a role in disease pathogenesis. We recently found that the cytokine TNFSF14/LIGHT is upregulated in the esophagus of patients with EoE and that LIGHT promotes inflammatory activity in esophageal fibroblasts. However, the global effects of LIGHT on EoE pathogenesis in vivo remain unknown. We investigated the impact of a LIGHT deficiency in a murine model of EoE driven by house dust mite allergen. Chronic intranasal challenge with house dust mite promoted esophageal eosinophilia and increased CD4+ T cell numbers and IL-13 and CCL11 production in wild-type mice. Esophageal remodeling was reflected by submucosal collagen accumulation, increased muscle density, and greater numbers of fibroblasts. LIGHT-/- mice displayed normal esophageal eosinophilia, but exhibited reduced frequencies of CD4 T cells, IL-13 expression, submucosal collagen, and muscle density and a decrease in esophageal accumulation of fibroblasts. In vitro, LIGHT increased division of human esophageal fibroblasts and selectively enhanced IL-13 -mediated expression of a subset of inflammatory and fibrotic genes. These results show that LIGHT contributes to various features of murine EoE, impacting the accumulation of CD4 T cells, IL-13 production, fibroblast proliferation, and esophagus remodeling. These findings suggest that LIGHT may be, to our knowledge, a novel therapeutic target for the treatment of EoE. The Journal of Immunology, 2022, 209: 2341-2351.