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

Barbara Spix, Elisabeth S. Butz, Cheng-Chang Chen, Anna Scotto Rosato, Rachel Tang, Aicha Jeridi, Veronika Kudrina, Eva Plesch, Philipp Wartenberg, Elisabeth Arlt, Daria Briukhovetska, Meshal Ansari, Gizem Günes Günsel, Thomas M. Conlon, Amanda Wyatt, Sandra Wetzel, Daniel Teupser, Lesca M. Holdt, Fabien Ectors, Ingrid Boekhoff, Ulrich Boehm, Jaime García-Añoveros, Paul Saftig, Martin Giera, Sebastian Kobold, Herbert B. Schiller, Susanna Zierler, Thomas Gudermann, Christian Wahl-Schott, Franz Bracher, Ali Önder Yildirim (), Martin Biel () and Christian Grimm ()
Additional contact information
Barbara Spix: Ludwig-Maximilians-University
Elisabeth S. Butz: Ludwig-Maximilians-University
Cheng-Chang Chen: Ludwig-Maximilians-University
Anna Scotto Rosato: Ludwig-Maximilians-University
Rachel Tang: Ludwig-Maximilians-University
Aicha Jeridi: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL)
Veronika Kudrina: Ludwig-Maximilians-University
Eva Plesch: Ludwig-Maximilians-University
Philipp Wartenberg: Saarland University, Center for Molecular Signaling (PZMS), Experimental Pharmacology
Elisabeth Arlt: Ludwig-Maximilians-University
Daria Briukhovetska: University Hospital Munich
Meshal Ansari: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL)
Gizem Günes Günsel: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL)
Thomas M. Conlon: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL)
Amanda Wyatt: Saarland University, Center for Molecular Signaling (PZMS), Experimental Pharmacology
Sandra Wetzel: Christian-Albrechts-University Kiel
Daniel Teupser: University Hospital Munich
Lesca M. Holdt: University Hospital Munich
Fabien Ectors: Liège University
Ingrid Boekhoff: Ludwig-Maximilians-University
Ulrich Boehm: Saarland University, Center for Molecular Signaling (PZMS), Experimental Pharmacology
Jaime García-Añoveros: Northwestern University, Feinberg School of Medicine
Paul Saftig: Christian-Albrechts-University Kiel
Martin Giera: Leiden University Medical Center
Sebastian Kobold: University Hospital Munich
Herbert B. Schiller: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL)
Susanna Zierler: Ludwig-Maximilians-University
Thomas Gudermann: Ludwig-Maximilians-University
Christian Wahl-Schott: Institute for Neurophysiology, Hannover Medical School
Franz Bracher: Ludwig-Maximilians-University
Ali Önder Yildirim: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL)
Martin Biel: Ludwig-Maximilians-University
Christian Grimm: Ludwig-Maximilians-University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-021-27860-x

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