Dataset Information

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 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.

SUBMITTER: Spix B

PROVIDER: S-EPMC8760276 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Spix Barbara B Butz Elisabeth S ES Chen Cheng-Chang CC Rosato Anna Scotto AS Tang Rachel R Jeridi Aicha A Kudrina Veronika V Plesch Eva E Wartenberg Philipp P Arlt Elisabeth E Briukhovetska Daria D Ansari Meshal M Günsel Gizem Günes GG Conlon Thomas M TM Wyatt Amanda A Wetzel Sandra S Teupser Daniel D Holdt Lesca M LM Ectors Fabien F Boekhoff Ingrid I Boehm Ulrich U García-Añoveros Jaime J Saftig Paul P Giera Martin M Kobold Sebastian S Schiller Herbert B HB Zierler Susanna S Gudermann Thomas T Wahl-Schott Christian C Bracher Franz F Yildirim Ali Önder AÖ Biel Martin M Grimm Christian C

Nature communications 20220114 1

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<sup>-/-</sup> mouse models enlarged lung injur ...[more]

PMID: 35031603

Similar Datasets

Project description:BackgroundChronic obstructive pulmonary disease (COPD) is among the top 5 causes of mortality in the world and can develop as a consequence of genetic and/or environmental factors. Current efforts are focused on identifying early life insults and how these contribute to COPD development. In line with this, our study focuses on the influence of early life nicotine exposure and its potential impact on (a) lung pulmonary functions, and (b) elastase-induced emphysema in adulthood.MethodsTo address this hypothesis, we developed a model of 2 hits, delivered at different time points: mouse pups were first exposed to nicotine/placebo in utero and during lactation, and then subsequently received elastase/placebo at the age of 11 weeks. The effect of nicotine pretreatment and elastase instillation was assessed by (a) measurement of pulmonary function at post-elastase day (ped) 21, and (b) transcriptomic profiling at ped3 and 21, and complementary protein determination. Statistical significance was determined by 3- and 2-way ANOVA for pulmonary functions, and RNAseq results were analyzed using the R project.ResultsWe did not observe any impact of nicotine pre- and early post-natal exposure compared to control samples on lung pulmonary functions in adulthood, as measured by FLEXIVENT technology. After elastase instillation, substantial lung damage was detected by x-ray tomography and was accompanied by loss in body weight at ped3 as well as an increase in cell numbers, inflammatory markers in BAL and lung volume at ped21. Lung functions showed a decrease in elastance and an increase in deep inflation volume and pressure volume (pv) loop area in animals with emphysema at ped21. Nicotine had no effect on elastance and deep inflation volume, but did affect the pv loop area in animals with emphysema at ped21. Extensive transcriptomic changes were induced by elastase at ped3 both in the nicotine-pretreated and the control samples, with several pathways common to both groups, such as for cell cycle, DNA adhesion and DNA damage. Nicotine pretreatment affected the number of lymphocytes present in BAL after elastase instillation and some of the complement pathway related proteins, arguing for a slight modification of the immune response, as well as changes related to general body metabolism. The majority of elastase-induced transcriptomic changes detected at ped3 had disappeared at ped21. In addition, transcriptomic profiling singled out a common gene pool that was independently activated by nicotine and elastase.ConclusionsOur study reports a broad spectrum of transient transcriptomic changes in mouse emphysema and identifies nicotine as influencing the emphysema-associated immune system response.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets