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

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.; Gunsel, G.G.; Conlon, T.M.; Wyatt, A.; Wetzel, S.; Teupser, D.; Holdt, L.M.; Ectors, F.; Boekhoff, I.; Boehm, U.; Garcia-Anoveros, J.; Saftig, P.; Giera, M.; Kobold, S.; Schiller, H.B.; Zierler, S.; Gudermann, T.; Wahl-Schott, C.; Bracher, F.; Yildirim, A.O.; Biel, M.; Grimm, C.

doi:doi:10.1038/s41467-021-27860-x

Excess macrophage elastase MMP-12 is a major driver of chronic obstructive pulmonary disease. Here the authors show that the endolysosomal ion channel TRPML3 is a regulator of the cellular reuptake of MMP-12, thus neutralizing harmful MMP-12 in the lung.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-tau GFP) reporter mouse model, transcriptomics, and endolysosomal patch-clamp experiments, we show that in the lung TRPML3 is...Show moreExcess macrophage elastase MMP-12 is a major driver of chronic obstructive pulmonary disease. Here the authors show that the endolysosomal ion channel TRPML3 is a regulator of the cellular reuptake of MMP-12, thus neutralizing harmful MMP-12 in the lung.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-tau GFP) 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.Show less

Leiden University Scholarly Publications

View statistics

Documents

In Collections

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