Macrophage expressed tartrate-resistant acid phosphatase 5 promotes pulmonary fibrosis progression
IMMUNOLOGY(2024)
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder involving scarring of pulmonary tissue and a subsequent decrease in respiratory capacity, ultimately resulting in death. Tartrate resistant acid phosphatase 5 (ACP5) plays a role in IPF but the exact mechanisms are yet to be elucidated. In this study, we have utilized various perturbations of the bleomycin mouse model of IPF including genetic knockout, RANKL inhibition, and macrophage adoptive transfer to further understand ACP5's role in pulmonary fibrosis. Genetic ablation of Acp5 decreased immune cell recruitment to the lungs and reduced the levels of hydroxyproline (reflecting extracellular matrix-production) as well as histological damage. Additionally, gene expression profiling of murine lung tissue revealed downregulation of genes including Ccl13, Mmp13, and Il-1 alpha that encodes proteins specifically related to immune cell recruitment and macrophage/fibroblast interactions. Furthermore, antibody-based neutralization of RANKL, an important inducer of Acp5 expression, reduced immune cell recruitment but did not decrease fibrotic lung development. Adoptive transfer of Acp5-/- bone marrow-derived monocyte (BMDM) macrophages 7 or 14 days after bleomycin administration resulted in reductions of cytokine production and decreased levels of lung damage, compared to adoptive transfer of WT control macrophages. Taken together, the data presented in this study suggest that macrophage derived ACP5 plays an important role in development of pulmonary fibrosis and could present a tractable target for therapeutic intervention in IPF. The macrophage expressed protein ACP5 plays an important role during recruitment of immune cells to the lung lumen. Administration of bleomycin to the lungs of mice results in symptoms that resembles idiopathic pulmonary fibrosis (IPF) in humans. Mice lacking ACP5 expression are protected against bleomycin induced weight loss and formation of fibrotic areas in the lungs. Additionally, immune cell recruitment and subsequent release of pro-inflammatory cytokines are both diminished in the ACP5 deficient mice. Taken together, macrophage-derived ACP5 plays an important role in IPF and could present a tractable therapeutic target for therapeutic intervention.image
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Key words
ACP5,immune cell recruitment,IPF,macrophages,RANKL,tartrate-resistant acid phosphatase (ACP5)
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