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; Christian Grimm

doi:10.1038/s41467-021-27860-x

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 BoekhoffUlrich 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, Christian Grimm

Institute of Pharmacology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	318
Number of pages	18
Journal	nature communications
DOIs	https://doi.org/10.1038/s41467-021-27860-x
Publication status	Published - Jan 2022

Fields of science

301206 Pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-021-27860-x

Cite this

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., ... Grimm, C. (2022). Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice. nature communications, Article 318. https://doi.org/10.1038/s41467-021-27860-x

@article{ec7df535ab0544d89af5778a661502b2,

title = "Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice",

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.",

author = "Barbara Spix and Butz, \{Elisabeth S.\} and Cheng-Chang Chen and Rosato, \{Anna Scotto\} and Rachel Tang and Aicha Jeridi and Veronika Kudrina and Eva Plesch and Philipp Wartenberg and Elisabeth Arlt and Daria Briukhovetska and Meshal Ansari and G{\"u}nsel, \{Gizem G{\"u}nes\} and Conlon, \{Thomas M.\} and Amanda Wyatt and Sandra Wetzel and Daniel Teupser and Holdt, \{Lesca M.\} and Fabien Ectors and Ingrid Boekhoff and Ulrich Boehm and Jaime Garc{\'i}a-A{\~n}overos and Paul Saftig and Martin Giera and Sebastian Kobold and Schiller, \{Herbert B.\} and Susanna Zierler and Thomas Gudermann and Christian Wahl-Schott and Franz Bracher and Yildirim, \{Ali {\"O}nder\} and Martin Biel and Christian Grimm",

year = "2022",

month = jan,

doi = "10.1038/s41467-021-27860-x",

language = "English",

journal = "nature communications",

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Spix, B, Butz, ES, Chen, C-C, Rosato, AS, Tang, R, Jeridi, A, Kudrina, V, Plesch, E, Wartenberg, P, Arlt, E, Briukhovetska, D, Ansari, M, Günsel, GG, Conlon, TM, Wyatt, A, Wetzel, S, Teupser, D, Holdt, LM, Ectors, F, Boekhoff, I, Boehm, U, García-Añoveros, J, Saftig, P, Giera, M, Kobold, S, Schiller, HB, Zierler, S, Gudermann, T, Wahl-Schott, C, Bracher, F, Yildirim, AÖ, Biel, M & Grimm, C 2022, 'Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice', nature communications. https://doi.org/10.1038/s41467-021-27860-x

TY - JOUR

T1 - Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice

AU - Spix, Barbara

AU - Butz, Elisabeth S.

AU - Chen, Cheng-Chang

AU - Rosato, Anna Scotto

AU - Tang, Rachel

AU - Jeridi, Aicha

AU - Kudrina, Veronika

AU - Plesch, Eva

AU - Wartenberg, Philipp

AU - Arlt, Elisabeth

AU - Briukhovetska, Daria

AU - Ansari, Meshal

AU - Günsel, Gizem Günes

AU - Conlon, Thomas M.

AU - Wyatt, Amanda

AU - Wetzel, Sandra

AU - Teupser, Daniel

AU - Holdt, Lesca M.

AU - Ectors, Fabien

AU - Boekhoff, Ingrid

AU - Boehm, Ulrich

AU - García-Añoveros, Jaime

AU - Saftig, Paul

AU - Giera, Martin

AU - Kobold, Sebastian

AU - Schiller, Herbert B.

AU - Zierler, Susanna

AU - Gudermann, Thomas

AU - Wahl-Schott, Christian

AU - Bracher, Franz

AU - Yildirim, Ali Önder

AU - Biel, Martin

AU - Grimm, Christian

PY - 2022/1

Y1 - 2022/1

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-021-27860-x

DO - 10.1038/s41467-021-27860-x

M3 - Article

SN - 2041-1723

JO - nature communications

JF - nature communications

M1 - 318

ER -