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^*

^*Corresponding author for this work

Anesthesiology

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

37 Scopus citations

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 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.

Original language	English (US)
Article number	318
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-27860-x
State	Published - Dec 2022

Funding

The authors gratefully acknowledge the help of Christine Hollauer, Alina Nakhabina, Wolfgang Wilfert, Armin Braun, and Christina Hesse. The authors further acknowledge the iFlow Core Facility of the University Hospital Munich for assistance with the generation of flow cytometry data. This work was supported, in part, by funding of the German Research Foundation (GRK2338 P08 to C.G. and M.B., and P09 to T.G., SFB/ TRR152 Z02 to U.B., P04 to C.G., P06 to C.W.-S., P12 to M.B., P15 and the German Center of Lung Research (DZL) to T.G., and R01 DK111032 and R01 DC015903 from NIH to J.G.-A. S.K is supported by the German Research Foundation, the Marie-Sklodowska-Curie Program Training Network for Optimizing Adoptive T Cell Therapy of Cancer funded by the H2020 Program of the European Union (Grant 955575) and the European Research Council Starting Grant (grant number 756017). C.-C.C. is supported by the National Taiwan University NTU-110L7906 and the Ministry of Science and Technology, R.O.C. Taiwan, Special Outstanding Award.

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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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., ... Grimm, C. (2022). Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice. Nature communications, 13(1), Article 318. https://doi.org/10.1038/s41467-021-27860-x

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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 Chen, {Cheng Chang} 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",

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

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Spix, B, Butz, ES, Chen, CC, 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, vol. 13, no. 1, 318. https://doi.org/10.1038/s41467-021-27860-x

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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 - 2022/12

Y1 - 2022/12

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.

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

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