Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice
Journal
Nature communications
Journal Volume
13
Journal Issue
1
Date Issued
2022
Author(s)
Spix, Barbara
Butz, Elisabeth S
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
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.
Subjects
SERIES MATRIX METALLOPROTEINASES; SMOKE-INDUCED EMPHYSEMA; ALVEOLAR MACROPHAGES; AUTOPHAGY; SURFACTANT; DISEASE; MMP-12; INFLAMMATION; EXPRESSION; PLASTICITY
SDGs
Publisher
NATURE PORTFOLIO
Type
journal article