Plasticity between type 2 innate lymphoid cell subsets and amphiregulin expression regulates epithelial repair in biliary atresia
Plasticity between type 2 innate lymphoid cell subsets and amphiregulin expression regulates epithelial repair in biliary atresia
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先天性2型淋巴细胞亚群与双调蛋白表达之间的可塑性调节胆道闭锁上皮修复
DOI：
10.1097/hep.0000000000000418
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发表时间：
2023-04
期刊：
影响因子：
13.5
通讯作者：
A. Russi;P. Shivakumar;Zhenhua Luo;J. Bezerra
中科院分区：
文献类型：
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作者：
A. Russi;P. Shivakumar;Zhenhua Luo;J. Bezerra
背景和目的：虽然失调的1型免疫反应是胆道闭锁发病机制的组成部分，但在人类和小鼠的研究中发现了主要由2型先天淋巴样细胞驱动的2型免疫反应。在非肝组织中，天然2型先天淋巴样细胞（nILC2s）调节上皮细胞增殖和组织修复，而炎性ILC2s （iIlC2s）驱动组织炎症和损伤。本研究的目的是确定2型先天淋巴样细胞（ILC2）亚群调节胆道上皮对损伤反应的机制。方法与结果：采用Spearman相关分析，在胆道闭锁患者诊断时，nILC2转录本与胆管细胞丰度呈正相关，而非iILC2s转录本。通过流式细胞术在小鼠肝脏中鉴定出nILC2s。在给予IL-33后，它们的双调节蛋白的产生增加。这通过nILC2s的减少和敲除菌株中上皮细胞增殖的减少来确定，通过IL-13/IL-4Rα/STAT6途径驱动上皮细胞增殖。IL-2的加入促进了nILC2表型的谱系间可塑性。在轮状病毒诱导的实验性胆道闭锁中，该通路促进上皮修复和组织再生。该回路的任何部分的遗传缺失或分子抑制都会将nILC2s转换为炎性2型先天淋巴样细胞，导致双调节蛋白产生减少，上皮细胞增殖减少，以及实验性胆道闭锁的全表型。结论：这些发现确定了IL-13/IL-4Rα/STAT6通路在ILC2可塑性中的关键功能，以及IL-2驱动的促进nILC2稳定性和双调节蛋白表达的交替回路。该途径诱导实验性胆道闭锁的上皮稳态和修复。
Background and Aims: Although a dysregulated type 1 immune response is integral to the pathogenesis of biliary atresia, studies in both humans and mice have uncovered a type 2 response, primarily driven by type 2 innate lymphoid cells. In nonhepatic tissues, natural type 2 innate lymphoid cell (nILC2s) regulate epithelial proliferation and tissue repair, whereas inflammatory ILC2s (iIlC2s) drive tissue inflammation and injury. The aim of this study is to determine the mechanisms used by type 2 innate lymphoid cell (ILC2) subpopulations to regulate biliary epithelial response to an injury. Approach and Results: Using Spearman correlation analysis, nILC2 transcripts, but not those of iILC2s, are positively associated with cholangiocyte abundance in biliary atresia patients at the time of diagnosis. nILC2s are identified in the mouse liver through flow cytometry. They undergo expansion and increase amphiregulin production after IL-33 administration. This drives epithelial proliferation dependent on the IL-13/IL-4Rα/STAT6 pathway as determined by decreased nILC2s and reduced epithelial proliferation in knockout strains. The addition of IL-2 promotes inter-lineage plasticity towards a nILC2 phenotype. In experimental biliary atresia induced by rotavirus, this pathway promotes epithelial repair and tissue regeneration. The genetic loss or molecular inhibition of any part of this circuit switches nILC2s to inflammatory type 2 innate lymphoid cell-like, resulting in decreased amphiregulin production, decreased epithelial proliferation, and the full phenotype of experimental biliary atresia. Conclusions: These findings identify a key function of the IL-13/IL-4Rα/STAT6 pathway in ILC2 plasticity and an alternate circuit driven by IL-2 to promote nILC2 stability and amphiregulin expression. This pathway induces epithelial homeostasis and repair in experimental biliary atresia.