Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice

Spix, Barbara; Butz, Elisabeth S.; Chen, Cheng-Chang; 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 und Grimm, Christian (2022): Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice. In: Nature Communications, Bd. 13, 318

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 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Walther-Straub-Institut für Pharmakologie und Toxikologie
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892