https://scholars.lib.ntu.edu.tw/handle/123456789/610547
標題: | Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice | 作者: | Spix, Barbara Butz, Elisabeth S CHENG-CHANG CHEN Rosato, Anna Scotto Tang, Rachel Jeridi, Aicha Kudrina, Veronika Plesch, Eva Wartenberg, Philipp Arlt, Elisabeth Briukhovetska, Daria Ansari, Meshal Günsel, Gizem Günes Conlon, Thomas M Wyatt, Amanda Wetzel, Sandra Teupser, Daniel Holdt, Lesca M Ectors, Fabien Boekhoff, Ingrid Boehm, Ulrich García-Añoveros, Jaime Saftig, Paul Giera, Martin Kobold, Sebastian Schiller, Herbert B Zierler, Susanna Gudermann, Thomas Wahl-Schott, Christian Bracher, Franz Yildirim, Ali Önder Biel, Martin Grimm, Christian |
關鍵字: | SERIES MATRIX METALLOPROTEINASES; SMOKE-INDUCED EMPHYSEMA; ALVEOLAR MACROPHAGES; AUTOPHAGY; SURFACTANT; DISEASE; MMP-12; INFLAMMATION; EXPRESSION; PLASTICITY | 公開日期: | 2022 | 出版社: | NATURE PORTFOLIO | 卷: | 13 | 期: | 1 | 來源出版物: | Nature communications | 摘要: | Lung emphysema and chronic bronchitis are the two most common causes of chronic obstructive pulmonary disease. Excess macrophage elastase MMP-12, which is predominantly secreted from alveolar macrophages, is known to mediate the development of lung injury and emphysema. Here, we discovered the endolysosomal cation channel mucolipin 3 (TRPML3) as a regulator of MMP-12 reuptake from broncho-alveolar fluid, driving in two independently generated Trpml3-/- mouse models enlarged lung injury, which is further exacerbated after elastase or tobacco smoke treatment. Mechanistically, using a Trpml3IRES-Cre/eR26-τGFP reporter mouse model, transcriptomics, and endolysosomal patch-clamp experiments, we show that in the lung TRPML3 is almost exclusively expressed in alveolar macrophages, where its loss leads to defects in early endosomal trafficking and endocytosis of MMP-12. Our findings suggest that TRPML3 represents a key regulator of MMP-12 clearance by alveolar macrophages and may serve as therapeutic target for emphysema and chronic obstructive pulmonary disease. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/610547 | ISSN: | 2041-1723 | DOI: | 10.1038/s41467-021-27860-x |
顯示於: | 醫學檢驗暨生物技術學系 |
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