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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, A.Ö. ; Biel, M.* ; Grimm, C.*

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

Nat. Commun. 13:318 (2022)
Publ. Version/Full Text Research data DOI
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Series Matrix Metalloproteinases; Smoke-induced Emphysema; Alveolar Macrophages; Autophagy; Surfactant; Disease; Mmp-12; Inflammation; Expression; Plasticity
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Quellenangaben Volume: 13, Issue: 1, Pages: , Article Number: 318 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Grants Ministry of Science and Technology, Taiwan
EC | European Research Council (ERC)
H2020 Program of the European Union
German Center of Lung Research (DZL)
Deutsche Forschungsgemeinschaft (German Research Foundation)
National Taiwan University
Deutsches Zentrum für Lungenforschung