Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice. Spix, B., Butz, E. S., Chen, C., Rosato, A. S., Tang, R., Jeridi, A., Kudrina, V., Plesch, E., Wartenberg, P., Arlt, E., Briukhovetska, D., Ansari, M., Günsel, G. G., Conlon, T. M., Wyatt, A., Wetzel, S., Teupser, D., Holdt, L. M., Ectors, F., Boekhoff, I., Boehm, U., García-Añoveros, J., Saftig, P., Giera, M., Kobold, S., Schiller, H. B., Zierler, S., Gudermann, T., Wahl-Schott, C., Bracher, F., Yildirim, A. Ö., Biel, M., & Grimm, C. Nature Communications, 13(1):318, January, 2022.
Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice [link]Paper  doi  abstract   bibtex   
Abstract 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 Trpml3 IRES-Cre/eR26- τ GFP 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.
@article{spix_lung_2022,
	title = {Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice},
	volume = {13},
	issn = {2041-1723},
	url = {https://www.nature.com/articles/s41467-021-27860-x},
	doi = {10.1038/s41467-021-27860-x},
	abstract = {Abstract
            
              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
              Trpml3
              
                IRES-Cre/eR26-
                τ
                GFP
              
              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.},
	language = {en},
	number = {1},
	urldate = {2024-06-10},
	journal = {Nature Communications},
	author = {Spix, Barbara and Butz, Elisabeth S. and Chen, Cheng-Chang and Rosato, Anna Scotto and Tang, Rachel and Jeridi, Aicha and Kudrina, Veronika and Plesch, Eva and Wartenberg, Philipp and Arlt, Elisabeth and Briukhovetska, Daria and Ansari, Meshal and Günsel, Gizem Günes and Conlon, Thomas M. and Wyatt, Amanda and Wetzel, Sandra and Teupser, Daniel and Holdt, Lesca M. and Ectors, Fabien and Boekhoff, Ingrid and Boehm, Ulrich and García-Añoveros, Jaime and Saftig, Paul and Giera, Martin and Kobold, Sebastian and Schiller, Herbert B. and Zierler, Susanna and Gudermann, Thomas and Wahl-Schott, Christian and Bracher, Franz and Yildirim, Ali Önder and Biel, Martin and Grimm, Christian},
	month = jan,
	year = {2022},
	pages = {318},
}
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