TRPML1 suppresses pulmonary fibrosis by limiting collagen and elastin deposition

TL;DR

TRPML1 prevents lung fibrosis by controlling the release of enzymes that break down collagen and elastin in the lungs.

Contribution

TRPML1 is newly identified as a regulator of matrix metalloproteinase exocytosis in lung cells, offering potential therapeutic strategies for pulmonary fibrosis.

Findings

TRPML1 loss in mice causes a fibrosis-like lung phenotype.

TRPML1 regulates exocytosis of multiple MMPs involved in ECM degradation.

TRPML1 agonists restore MMP exocytosis in macrophages and fibroblasts.

Abstract

In pulmonary fibrosis lung tissue is thickened and scarred, and the lungs become progressively stiffer and smaller, leading to low levels of blood oxygen and shortness of breath. Lung fibrosis is not curable and life expectancy is reduced. Fibrosis is characterized by an increased accumulation of extracellular matrix (ECM) proteins such as collagen and elastin. ECM proteins are degraded predominantly by matrix metalloproteinases (MMPs). Here, we show that the lysosomal cation channel TRPML1, which causes the lysosomal storage disorder mucolipidosis type IV (MLIV) when mutated or lost, regulates the levels of MMPs in the ECM of mouse airways, modulating exocytosis of MMP2, 8, 9, 12, and 19, which mediate collagen/elastin degradation. While TRPML1 loss reduces MMP levels in lung macrophage and fibroblast supernatants, small molecule activation of TRPML1 results in increased levels. MLIV mice display a fibrosis-like lung phenotype similar to the phenotype evoked by bleomycin. We thus identify TRPML1 as a regulator of MMP release in the lung with loss of TRPML1 resulting in lung fibrosis due to excessive extracellular collagen and elastin accumulation.

Lung fibrosis emerges from an imbalance between extracellular matrix (ECM) component deposition and matrix protease function, but its causal determinants remain incompletely understood. This study identifies endolysosomal cation channel TRPML1 as a regulator of matrix metalloproteinase (MMP) exocytosis in alveolar cells, suggesting novel therapeutic avenues for pulmonary disease.

TRPML1 depletion or TRPML1 mutation in lysosomal storage disorder mucolipidosis type IV (MLIV) mice induces a fibrosis-like pulmonary phenotype.TRPML1 depletion disrupts lysosomal exocytosis of MMPs and impairs collagen degradation in alveolar fibroblasts and macrophages.Newly developed TRPML1 agonists rescue MMP exocytosis in isolated macrophages and fibroblasts.

TRPML1 depletion or TRPML1 mutation in lysosomal storage disorder mucolipidosis type IV (MLIV) mice induces a fibrosis-like pulmonary phenotype.

TRPML1 depletion disrupts lysosomal exocytosis of MMPs and impairs collagen degradation in alveolar fibroblasts and macrophages.

Newly developed TRPML1 agonists rescue MMP exocytosis in isolated macrophages and fibroblasts.

Endolysosomal cation channel TRPML1 safeguards matrix protease exocytosis and extracellular matrix turnover in the airways.

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