抑制LTβR信號激活WNT誘導的肺再生
作者：
小柯機器人發布時間：2020/11/6 20:02:23
德國肺臟研究中心（DZL）Ali Önder Yildirim課題組近日取得一項新成果。他們的研究顯示，抑制淋巴毒素β受體（LTβR）信號激活WNT誘導的肺再生。相關論文在線發表在2020年11月4日出版的《自然》雜誌上。
研究人員發現在與吸菸相關慢性阻塞性肺疾病（COPD）患者和長期接觸香菸煙霧小鼠的肺上皮細胞中LTβR配體在先天免疫和適應性免疫細胞中高表達，還表現出增強的非典型NF-κB信號以及 LTβR目的基因的高表達。在年輕和老年小鼠中，利用藥物抑制LTβR信號破壞了與吸菸有關的可誘導支氣管相關淋巴組織並有利於肺組織的再生、恢復了氣道纖維化和全身性肌肉消瘦。
從機制上講，LTβR信號傳導的阻滯減弱了上皮細胞非典型NF-κB的激活、減少了氣道中的TGFβ信號傳導並通過防止上皮細胞死亡和激活肺泡上皮祖細胞的WNT /β-catenin信號來誘導再生。
這些發現表明，抑制LTβR信號可能是一種可行的治療手段，其阻礙了三維淋巴結構的形成、細胞凋亡以及促進了組織再生。
據悉，LTβR信號會促進淋巴新生並形成三維淋巴結構，這與跨多個器官系統的嚴重慢性炎性疾病有關。尚不清楚LTβR信號如何誘導慢性組織損傷（尤其是在肺部）、調節該過程的機制以及LTβR阻滯是否具有治療價值。
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