Lo Bernard C, Gold Matthew J, Hughes Michael R, Antignano Frann, Valdez Yanet, Zaph Colby, Harder Kenneth W, McNagny Kelly M
The Biomedical Research Centre, University of British Columbia, V6T 1Z3.
STEMCELL Technologies Incorporated, Vancouver, British Columbia, V6A 1B6.
Sci Immunol. 2016 Sep 2;1(3). doi: 10.1126/sciimmunol.aaf8864.
Fibrosis is the result of dysregulated tissue regeneration and is characterized by excessive accumulation of matrix proteins that become detrimental to tissue function. In Crohn's disease, this manifests itself as recurrent gastrointestinal strictures for which there is no effective therapy beyond surgical intervention. Using a model of infection-induced chronic gut inflammation, we show that -deficient mice are protected from fibrosis; infected intestinal tissues display diminished pathology, attenuated collagen deposition and reduced fibroblast accumulation. Although is best known for its role in ILC2 development, we find that -induced fibrosis is independent of eosinophils, STAT6 signaling and Th2 cytokine production arguing that this process is largely ILC2-independent. Instead, we observe reduced levels of ILC3- and T cell-derived IL-17A and IL-22 in infected gut tissues. Furthermore, using / bone marrow chimeric mice, we show that restoring ILC function is sufficient to re-establish IL-17A and IL-22 production and a profibrotic phenotype. Our results show that RORα-dependent ILC3 functions are pivotal in mediating gut fibrosis and they offer an avenue for therapeutic intervention in Crohn's-like diseases.
纤维化是组织再生失调的结果，其特征是基质蛋白过度积累，进而对组织功能产生有害影响。在克罗恩病中，这表现为反复出现的胃肠道狭窄，除手术干预外，尚无有效的治疗方法。利用感染诱导的慢性肠道炎症模型，我们发现缺乏 的小鼠可免受纤维化影响；受感染的肠道组织病理变化减轻、胶原蛋白沉积减少且成纤维细胞积累减少。尽管 因其在2型固有淋巴细胞（ILC2）发育中的作用而最为人所知，但我们发现 诱导的纤维化与嗜酸性粒细胞、信号转导及转录激活因子6（STAT6）信号传导和2型辅助性T细胞（Th2）细胞因子产生无关，这表明该过程在很大程度上不依赖ILC2。相反，我们观察到受感染肠道组织中3型固有淋巴细胞（ILC3）和T细胞衍生的白细胞介素-17A（IL-17A）和白细胞介素-22（IL-22）水平降低。此外，利用 / 骨髓嵌合小鼠，我们表明恢复ILC功能足以重新建立IL-17A和IL-22的产生以及促纤维化表型。我们的结果表明，依赖维甲酸相关孤儿受体α（RORα）的ILC3功能在介导肠道纤维化中起关键作用，并且为克罗恩病样疾病的治疗干预提供了一条途径。
