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

[en] 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.

Disciplines :

Biotechnology

Author, co-author :

Spix, Barbara

Butz, Elisabeth

Chen, Cheng-Chang

Scotto Rosato, Anna

Tang, Rachel

Jeridi

Kudrina, Veronika

Plesch, Eva

Wartenberg, Philipp

Arlt, Elisabeth

More authors (22 more)

Language :

English

Title :

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

Publication date :

14 January 2022

Journal title :

Nature Communications

eISSN :

2041-1723

Publisher :

Nature Publishing Group, United Kingdom

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

DFG - Deutsche Forschungsgemeinschaft [DE]

Funding text :

Deutsche Forschungsgemeinschaft (German Research Foundation) - GRK2338 [Grimm]

Data Set :

10.1038/s41467-021-27860-x

Available on ORBi :

since 09 February 2022

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