TRAPping the effects of tobacco smoking: the regulation and function of Acp5 expression in lung macrophages.

IF 3.6 2区 医学 Q1 PHYSIOLOGY
Suzanne H Willems, Shilei Qian, Pernilla Lång, Bjarne E Overtoom, Sina Alimostafazadeh, Rocío Fuentes-Mateos, Gwenda F Vasse, T Anienke van der Veen, Jelmer Vlasma, Marina H de Jager, Victor Guryev, Gyorgy Fejer, Göran Andersson, Barbro N Melgert
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引用次数: 0

Abstract

Tartrate-resistant acid phosphatase [TRAP, gene acid phosphatase 5 (Acp5; gene name for TRAP)] is highly expressed in alveolar macrophages with proposed roles in lung inflammation and lung fibrosis development. We previously showed that its expression and activity are higher in lung macrophages of smokers and patients with chronic obstructive pulmonary disease (COPD), suggesting involvement in smoke-induced lung damage. In this study, we explored the function of TRAP and regulation of its different mRNA transcripts (Acp5 201-206) in lung tissue exposed to cigarette smoke to elucidate its function in alveolar macrophages. In mice exposed to cigarette smoke or air for 4-6 wk, higher Acp5 mRNA expression in lung tissue after smoking was mainly driven by transcript Acp5-202, which originates from macrophages. The expression of Acp5-202 correlated with transcription factors previously found to drive proliferation of macrophages. Treating fetal liver progenitor-derived alveolar-like macrophages [Max Planck Institute (MPI; macrophages derived from fetal liver progenitors) macrophages] with cigarette smoke extract resulted in more proliferation compared with nontreated cells. In contrast, Acp5-deficient MPI macrophages and MPI macrophages treated with a TRAP inhibitor proliferated significantly less than control macrophages. Mechanistically, this lack of proliferation after TRAP inhibition was associated with higher presence of phosphorylated Beta-catenin (β-catenin; a signaling protein) compared with nontreated controls. Phosphorylation of β-catenin is known to mark it for ubiquitination and degradation by the proteasome, preventing its activity in promoting cell proliferation. In conclusion, our findings provide strong evidence for TRAP stimulating alveolar macrophage proliferation by dephosphorylating β-catenin. By driving proliferation, TRAP likely helps sustain alveolar macrophage populations during smoke exposure, either compensating for their loss due to smoking or increasing their numbers to better manage smoke-induced damage.NEW & NOTEWORTHY This study has uncovered that the enzyme tartrate-resistant acid phosphatase (TRAP) is crucial for alveolar macrophage proliferation through a β-catenin-dependent pathway. Importantly, TRAP influences this important ability of alveolar macrophages through the Acp5-202 mRNA transcript. The increase in TRAP expression following smoke exposure suggests that it plays a key role in promoting cell renewal, potentially helping to mitigate smoke-induced lung damage.

捕获吸烟的影响:肺巨噬细胞中Acp5表达的调控和功能。
抗酒石酸酸性磷酸酶(TRAP,基因Acp5)在肺泡巨噬细胞中高表达,并在肺部炎症和肺纤维化发展中发挥作用。我们之前的研究表明,它在吸烟者和COPD患者的肺巨噬细胞中的表达和活性更高,表明它参与了烟雾引起的肺损伤。在这项研究中,我们探讨了TRAP及其不同mRNA转录本(Acp5 201-206)在暴露于香烟烟雾的肺组织中的功能及其调控,以阐明其在肺泡巨噬细胞中的功能。在暴露于香烟烟雾或空气4-6周的小鼠中,吸烟后肺组织中Acp5 mRNA的表达升高主要是由来自巨噬细胞的转录本Acp5-202驱动的。Acp5-202的表达与先前发现的驱动巨噬细胞增殖的转录因子相关。与未处理的细胞相比,香烟烟雾提取物处理胎儿肝脏祖细胞衍生的肺泡样巨噬细胞(MPI巨噬细胞)可导致更多的增殖。相比之下,acp5缺陷的MPI巨噬细胞和TRAP抑制剂处理的MPI巨噬细胞的增殖明显低于对照巨噬细胞。与未处理的对照组相比,TRAP抑制后的增殖缺乏与磷酸化β-连环蛋白的较高存在有关。已知β-catenin的磷酸化标志着它被蛋白酶体泛素化和降解,从而阻止其促进细胞增殖的活性。总之,我们的研究结果为TRAP通过去磷酸化β-catenin刺激肺泡巨噬细胞增殖提供了强有力的证据。通过促进增殖,TRAP可能有助于在烟雾暴露期间维持肺泡巨噬细胞的数量,或者补偿吸烟造成的损失,或者增加它们的数量以更好地管理烟雾引起的损伤。
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来源期刊
CiteScore
9.20
自引率
4.10%
发文量
146
审稿时长
2 months
期刊介绍: The American Journal of Physiology-Lung Cellular and Molecular Physiology publishes original research covering the broad scope of molecular, cellular, and integrative aspects of normal and abnormal function of cells and components of the respiratory system. Areas of interest include conducting airways, pulmonary circulation, lung endothelial and epithelial cells, the pleura, neuroendocrine and immunologic cells in the lung, neural cells involved in control of breathing, and cells of the diaphragm and thoracic muscles. The processes to be covered in the Journal include gas-exchange, metabolic control at the cellular level, intracellular signaling, gene expression, genomics, macromolecules and their turnover, cell-cell and cell-matrix interactions, cell motility, secretory mechanisms, membrane function, surfactant, matrix components, mucus and lining materials, lung defenses, macrophage function, transport of salt, water and protein, development and differentiation of the respiratory system, and response to the environment.
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