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-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.
- Spix, B.
- Butz, E. S.
- Chen, C. C.
- Rosato, A. S.
- Tang, R.
- Jeridi, A.
- Kudrina, V.
- Plesch, E.
- Wartenberg, P.
- Arlt, E.
- Briukhovetska, D.
- Ansari, M.
- Günsel, G. G.
- Conlon, T. M.
- Wyatt, A.
- Wetzel, S.
- Teupser, D.
- Holdt, L. M.
- Ectors, F.
- Boekhoff, I.
- Boehm, U.
- García-Añoveros, J.
- Saftig, P.
- Giera, M.
- Kobold, S.
- Schiller, H. B.
- Zierler, S.
- Gudermann, T.
- Wahl-Schott, C.
- Bracher, F.
- Yildirim, AÖ
- Biel, M.
- Grimm, C.
