小柯机器人

德国肺脏研究中心（DZL）Ali Önder Yildirim课题组近日取得一项新成果。他们的研究显示，抑制淋巴毒素β受体（LTβR）信号激活WNT诱导的肺再生。相关论文在线发表在2020年11月4日出版的《自然》杂志上。

研究人员发现在与吸烟相关慢性阻塞性肺疾病（COPD）患者和长期接触香烟烟雾小鼠的肺上皮细胞中LTβR配体在先天免疫和适应性免疫细胞中高表达，还表现出增强的非典型NF-κB信号以及 LTβR目的基因的高表达。在年轻和老年小鼠中，利用药物抑制LTβR信号破坏了与吸烟有关的可诱导支气管相关淋巴组织并有利于肺组织的再生、恢复了气道纤维化和全身性肌肉消瘦。

从机制上讲，LTβR信号传导的阻滞减弱了上皮细胞非典型NF-κB的激活、减少了气道中的TGFβ信号传导并通过防止上皮细胞死亡和激活肺泡上皮祖细胞的WNT /β-catenin信号来诱导再生。

这些发现表明，抑制LTβR信号可能是一种可行的治疗手段，其阻碍了三维淋巴结构的形成、细胞凋亡以及促进了组织再生。

据悉，LTβR信号会促进淋巴新生并形成三维淋巴结构，这与跨多个器官系统的严重慢性炎性疾病有关。尚不清楚LTβR信号如何诱导慢性组织损伤（尤其是在肺部）、调节该过程的机制以及LTβR阻滞是否具有治疗价值。

附：英文原文

Title: Inhibition of LTβR signalling activates WNT-induced regeneration in lung

Author: Thomas M. Conlon, Gerrit John-Schuster, Danijela Heide, Dominik Pfister, Mareike Lehmann, Yan Hu, Zeynep Ertz, Martin A. Lopez, Meshal Ansari, Maximilian Strunz, Christoph Mayr, Chiara Ciminieri, Rita Costa, Marlene Sophia Kohlhepp, Adrien Guillot, Gizem Gnes, Aicha Jeridi, Maja C. Funk, Giorgi Beroshvili, Sandra Prokosch, Jenny Hetzer, Stijn E. Verleden, Hani Alsafadi, Michael Lindner, Gerald Burgstaller, Lore Becker, Martin Irmler, Michael Dudek, Jakob Janzen, Eric Goffin, Reinoud Gosens, Percy Knolle, Bernard Pirotte, Tobias Stoeger, Johannes Beckers, Darcy Wagner, Indrabahadur Singh, Fabian J. Theis, Martin Hrab de Angelis, Tracy OConnor, Frank Tacke, Michael Boutros, Emmanuel Dejardin, Oliver Eickelberg, Herbert B. Schiller, Melanie Knigshoff, Mathias Heikenwalder, Ali nder Yildirim

Issue&Volume: 2020-11-04

Abstract: Lymphotoxin β-receptor (LTβR) signalling promotes lymphoid neogenesis and the development of tertiary lymphoid structures1,2, which are associated with severe chronic inflammatory diseases that span several organ systems3,4,5,6. How LTβR signalling drives chronic tissue damage particularly in the lung, the mechanism(s) that regulate this process, and whether LTβR blockade might be of therapeutic value have remained unclear. Here we demonstrate increased expression of LTβR ligands in adaptive and innate immune cells, enhanced non-canonical NF-κB signalling, and enriched LTβR target gene expression in lung epithelial cells from patients with smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke. Therapeutic inhibition of LTβR signalling in young and aged mice disrupted smoking-related inducible bronchus-associated lymphoid tissue, induced regeneration of lung tissue, and reverted airway fibrosis and systemic muscle wasting. Mechanistically, blockade of LTβR signalling dampened epithelial non-canonical activation of NF-κB, reduced TGFβ signalling in airways, and induced regeneration by preventing epithelial cell death and activating WNT/β-catenin signalling in alveolar epithelial progenitor cells. These findings suggest that inhibition of LTβR signalling represents a viable therapeutic option that combines prevention of tertiary lymphoid structures1 and inhibition of apoptosis with tissue-regenerative strategies.

DOI: 10.1038/s41586-020-2882-8

Source: https://www.nature.com/articles/s41586-020-2882-8

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