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 ; Grimm, Christian (2022): Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice. Nature Communications, 13: 318. ISSN 2041-1723

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.

• Doc-Type: Article (LMU)
• Organisational unit (Faculties): 07 Medicine > Walther Straub Institute of Pharmacology and toxicology
• DFG subject classification of scientific disciplines: Life sciences
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 491502892