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

• DOI: 10.1038/s41467-021-27860-x
• Publication Date: 2022-01-14T11:02:40Z
• Authors: Barbara Spix; Elisabeth S. Butz; Cheng-Chang Chen; Anna Scotto Rosato; Rachel Tang; Aicha Jeridi; Veronika Kudrina; Eva Plesch; Philipp Wartenberg; Elisabeth Arlt; Daria Briukhovetska; Meshal Ansari; Gizem Günes Günsel; Thomas M. Conlon; Amanda Wyatt; Sandra Wetzel; Daniel Teupser; Lesca M. Holdt; Fabien Ectors; Ingrid Boekhoff; Ulrich Boehm; Jaime García-Añov...; Paul Saftig; Martin Giera; Sebastian Kobold; Herbert B. Schiller; Susanna Zierler; Thomas Gudermann; Christian Wahl-Sc...; Franz Bracher; Ali Önder Yildirim; Martin Biel; Christian Grimm
• Keywords: Mice, Knockout; 0301 basic medicine; Pancreatic Elastase; Science; Q; Endosomes; Article; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Transient Receptor Potential Channels; Pulmonary Emphysema; Matrix Metalloproteinase 12; Macrophages, Alveolar; Animals; Humans; Female; Lung

AbstractLung 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.