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Spix, Barbara; Butz, Elisabeth S.; Chen, Cheng-Chang; Rosato, Anna Scotto; Tang, Rachel; Jeridi, Aicha; Kudrina, Veronika ORCID: 0000-0002-3762-8673; Plesch, Eva; Wartenberg, Philipp; Arlt, Elisabeth; Briukhovetska, Daria; Ansari, Meshal ORCID: 0000-0002-8819-7965; Günsel, Gizem Günes; Conlon, Thomas M. ORCID: 0000-0002-4316-6612; Wyatt, Amanda ORCID: 0000-0003-1107-3857; Wetzel, Sandra; Teupser, Daniel; Holdt, Lesca M.; Ectors, Fabien ORCID: 0000-0003-2846-7019; Boekhoff, Ingrid; Boehm, Ulrich; García-Añoveros, Jaime ORCID: 0000-0001-6561-9048; Saftig, Paul ORCID: 0000-0003-2637-7052; Giera, Martin ORCID: 0000-0003-1684-1894; Kobold, Sebastian ORCID: 0000-0002-5612-4673; Schiller, Herbert B. ORCID: 0000-0001-9498-7034; Zierler, Susanna; Gudermann, Thomas; Wahl-Schott, Christian ORCID: 0000-0002-7514-2367; Bracher, Franz ORCID: 0000-0003-0009-8629; Yildirim, Ali Önder ORCID: 0000-0003-1969-480X; Biel, Martin ORCID: 0000-0002-9974-3052; Grimm, Christian ORCID: 0000-0002-0177-5559 (2022): Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice. Nature Communications, 13: 318. ISSN 2041-1723

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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.

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