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

Nat Commun. 2022 Jan 14;13(1):318. doi: 10.1038/s41467-021-27860-x.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Endosomes / metabolism
  • Female
  • Humans
  • Lung / enzymology
  • Macrophages, Alveolar / enzymology*
  • Matrix Metalloproteinase 12 / genetics
  • Matrix Metalloproteinase 12 / metabolism*
  • Mice
  • Mice, Knockout
  • Pancreatic Elastase / genetics
  • Pancreatic Elastase / metabolism*
  • Pulmonary Emphysema / enzymology*
  • Pulmonary Emphysema / genetics
  • Pulmonary Emphysema / metabolism
  • Transient Receptor Potential Channels / deficiency*
  • Transient Receptor Potential Channels / genetics


  • Mcoln3 protein, mouse
  • Transient Receptor Potential Channels
  • Pancreatic Elastase
  • Matrix Metalloproteinase 12