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

Barbara Spix,Thomas M Conlon,Ali Önder Yildirim,Rachel Tang,Gizem Günes Günsel,Ingrid Boekhoff,Sebastian Kobold,Cheng‐Chang Chen ,Eva Plesch,Elisabeth Arlt,Aicha Jeridi,Susanna Zierler,Meshal Ansari,Fabien Ectors,Veronika Kudrina,Franz Bracher,Martin Giera,Amanda Wyatt,Philipp Wartenberg,Daniel Teupser,Sandra Wetzel,Anna Scotto Rosato,Christian Wahl‐Schott ,Jaime Garcı́a-Añoveros ,Paul Säftig ,Herbert B Schiller,Martin Biel,Ulrich Boehm,Lesca M Holdt,Thomas Gudermann,Elisabeth Butz ,Daria Briukhovetska,Christian Grimm

doi:10.1038/s41467-021-27860-x

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.

Highlights

Lung emphysema and chronic bronchitis are the two most common causes of chronic obstructive pulmonary disease
Loss of TRPML3 results in endocytosis and early endosomal trafficking defects in AMΦ which endocytose less MMP-12 upon blockade of clathrinindependent endocytosis in a TRPML3dependent manner, and more MMP-12 when activated with a selective TRPML3 agonist, highlighting a new mechanism involved in the regulation of MMP-12 levels in the extracellular matrix of the lungs
After blastocyst injection and germline transmission of the Trpml3-IRES-Cre allele, heterozygous Trpml3-IRES-Cre mice were crossed with FLP deleter mice

Summary

Introduction

Lung emphysema and chronic bronchitis are the two most common causes of chronic obstructive pulmonary disease. Results Trpml3IRES-Cre/eR26-τGFP reporter mouse model reveals selective expression of TRPML3 in AMΦ in the lung. This predominant and high expression of TRPML3 in AMΦ prompted us to assess the lung function in Trpml3−/− mouse models.

Results

Conclusion