LIGHT controls distinct homeostatic and inflammatory gene expression profiles in esophageal fibroblasts via differential HVEM and LTβR-mediated mechanisms.
LIGHT controls distinct homeostatic and inflammatory gene expression profiles in esophageal fibroblasts via differential HVEM and LTβR-mediated mechanisms.
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DOI：
10.1038/s41385-021-00472-w
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发表时间：
2022-03
影响因子：
8
通讯作者：
Aceves SS
中科院分区：
文献类型：
--
作者：
Manresa MC;Wu A;Nhu QM;Chiang AWT;Okamoto K;Miki H;Kurten R;Pham E;Duong LD;Lewis NE;Akuthota P;Croft M;Aceves SS
成纤维细胞介导嗜酸性食管炎(EoE)的组织重塑，EoE是一种由过敏原驱动的慢性炎性病理。不同的成纤维细胞亚型具有动态平衡调节或炎症的特征，已经在不同的组织中被识别，但哪些介体诱导这些交替的分化状态在很大程度上仍不清楚。我们最近发现，TNFSF14/LIGHT在体外可以促进炎性食道成纤维细胞的生长。在此，我们使用食道活检组织和原代成纤维细胞来研究光受体、疱疹病毒进入介质(HVEM)和淋巴毒素-β受体(LTβR)及其下游激活通路在EOE中的作用。除了促进炎症基因的表达外，LIGH还下调了包括WNTs、BMPs和3型信号素在内的动态平衡因子。在体内，EoE中WNT2B+的成纤维细胞减少，而ICAM-1+和IL-34+的成纤维细胞扩张，提示EoE与正常的食道成纤维细胞相比存在光驱动的基因信号。HVEM和LTβR的过度表达和缺乏实验表明，HVEM调节一小部分光靶标，而LTβR控制所有的转录效应。药物阻断非规范的NIK/P100/p52介导的NF-κB途径可以有效地沉默LIGH的转录效应，而p65规范的NF-κB的作用较小。总之，我们的结果表明LIGH促进食道成纤维细胞向炎症表型的分化，并通过LTβR-NIK-P52 NF-κB主导途径抑制动态平衡基因的表达。▓
Fibroblasts mediate tissue remodeling in eosinophilic esophagitis (EoE), a chronic allergen-driven inflammatory pathology. Diverse fibroblast subtypes with homeostasis-regulating or inflammatory profiles have been recognized in various tissues, but which mediators induce these alternate differentiation states remain largely unknown. We recently identified that TNFSF14/LIGHT promotes an inflammatory esophageal fibroblast in vitro. Herein we used esophageal biopsies and primary fibroblasts to investigate the role of the LIGHT receptors, herpes virus entry mediator (HVEM) and lymphotoxin-beta receptor (LTβR), and their downstream activated pathways, in EoE. In addition to promoting inflammatory gene expression, LIGHT down-regulated homeostatic factors including WNTs, BMPs and type 3 semaphorins. In vivo, WNT2B+ fibroblasts were decreased while ICAM-1+ and IL-34+ fibroblasts were expanded in EoE, suggesting that a LIGHT-driven gene signature was imprinted in EoE versus normal esophageal fibroblasts. HVEM and LTβR overexpression and deficiency experiments demonstrated that HVEM regulates a limited subset of LIGHT targets, whereas LTβR controls all transcriptional effects. Pharmacologic blockade of the non-canonical NIK/p100/p52-mediated NF-κB pathway potently silenced LIGHT’s transcriptional effects, with a lesser role found for p65 canonical NF-κB. Collectively, our results show that LIGHT promotes differentiation of esophageal fibroblasts toward an inflammatory phenotype and represses homeostatic gene expression via a LTβR-NIK-p52 NF-κB dominant pathway. ▓
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影响因子：
32.4
作者：
Dejardin, E;Droin, NM;Green, DR
通讯作者：
Green, DR
DOI：
10.4049/jimmunol.0902490
发表时间：
2009-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Cheung TC;Oborne LM;Steinberg MW;Macauley MG;Fukuyama S;Sanjo H;D'Souza C;Norris PS;Pfeffer K;Murphy KM;Kronenberg M;Spear PG;Ware CF
通讯作者：
Ware CF
影响因子：
14.9
作者：
Jensen LJ;Kuhn M;Stark M;Chaffron S;Creevey C;Muller J;Doerks T;Julien P;Roth A;Simonovic M;Bork P;von Mering C
通讯作者：
von Mering C
DOI：
10.1038/jid.2015.110
发表时间：
2015-08
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Herro R;Antunes RDS;Aguilera AR;Tamada K;Croft M
通讯作者：
Croft M
影响因子：
64.5
作者：
Kinchen J;Chen HH;Parikh K;Antanaviciute A;Jagielowicz M;Fawkner-Corbett D;Ashley N;Cubitt L;Mellado-Gomez E;Attar M;Sharma E;Wills Q;Bowden R;Richter FC;Ahern D;Puri KD;Henault J;Gervais F;Koohy H;Simmons A
通讯作者：
Simmons A