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Lung macrophages utilize unique cathepsin K-dependent phagosomal machinery to degrade intracellular collagen

ABSTRACT: Resident tissue macrophages (RTMs) are organ-specialized phagocytes responsible for the maintenance and protection of residing tissue. It is well established that tissue diversity is reflected by the heterogeneity of RTMs origin and phenotype. However, much less is known about tissue-specific phagocytic macrophage functions. Here, using quantitative proteomics approach, we identify cathepsins as key determinants of phagosome maturation in primary peritoneal, lung and brain resident macrophages. The data further uncover cathepsin K (CtsK) as a molecular marker for lung phagosomes required for intracellular protein and collagen degradation. Pharmacological blockade of CtsK activity diminished phagosomal proteolysis and collagenolysis in lung resident macrophages. Furthermore, pro-fibrotic TGF-β negatively regulated CtsK-mediated phagosomal collagen degradation independently from classical endocytic proteolytic pathways. In humans, phagosomal CtsK activity was reduced in lung COPD macrophages and lung macrophages exposed to cigarette smoke extract. Taken together, this study provides a comprehensive map of how peritoneal, lung and brain tissue environment shapes phagosomal composition of resident macrophages, revealing CtsK as a key molecular determinant of lung phagosomes contributing to phagocytic collagen clearance in lungs.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Lung, Peritoneum, Macrophage

SUBMITTER: Ivo Fabrik

LAB HEAD: Anetta Härtlova

PROVIDER: PXD033010 | Pride | 2023-01-18

REPOSITORIES: Pride

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