Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization

Our plain-English summary of Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization, by L. Gu, J.L. Larson-Casey, A.B. Carter (FASEB Journal, 2017).

The study

• Authors: L. Gu, J.L. Larson-Casey, A.B. Carter
• Journal: FASEB Journal
• Published: 2017;31(7):3072-3083
• Cited by: 42 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Fibrosis in multiple organs, including the liver, kidney, and lung, often occurs secondary to environmental exposure. Asbestos exposure is one important environmental cause of lung fibrosis. The mechanisms that mediate fibrosis is not fully understood, although mitochondrial oxidative stress in alveolar macrophages is critical for fibrosis development. Mitochondrial Ca2+ levels can be associated with production of reactive oxygen species. Here, we show that patients with asbestosis have higher levels of mitochondrial Ca2+ compared with normal patients. The mitochondrial calcium uniporter (MCU) is a highly selective ion channel that transports Ca2+ into the mitochondrial matrix to modulate metabolism. Asbestos exposure increased mitochondrial Ca2+ influx in alveolar macrophages from wild-type, but not MCU+/-, mice. MCU expression polarized macrophages to a profibrotic phenotype after exposure to asbestos, and the profibrotic polarization was regulated by MCU-mediated ATP production. Profibrotic polarization was abrogated when MCU was absent or its activity was blocked. Of more importance, mice that were deficient in MCU were protected from pulmonary fibrosis. Regulation of mitochondrial Ca2+ suggests that MCU may play a pivotal role in the development of fibrosis and could potentially be a therapeutic target for pulmonary fibrosis.-Gu, L., Larson-Casey, J. L., Carter, A. B. Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization.

© FASEB.

In plain English

This laboratory study looked at a protein called the mitochondrial calcium uniporter (MCU), which carries calcium into mitochondria, the energy-producing parts of cells. The authors asked whether MCU is needed for lung scarring (pulmonary fibrosis) caused by asbestos. They used cultured human monocyte cells and mouse alveolar macrophage cells (both immune cells), normal mice, mice partly lacking MCU, and lung-wash macrophages from normal participants and from patients with asbestosis. The asbestos used was Libby amphibole or chrysotile. Macrophages from patients with asbestosis had more MCU and more calcium in their mitochondria than those from normal participants. In cells and in mice, asbestos raised mitochondrial calcium, hydrogen peroxide production and ATP (energy) production. It also raised TGF-b1, a signal linked to scarring. These changes were reduced when MCU was lacking or blocked. Asbestos-exposed normal mice developed dense collagen in their lungs, while the MCU-deficient mice had essentially normal lung structure. The authors concluded that patients with pulmonary fibrosis have increased mitochondrial calcium in alveolar macrophages and that MCU deficiency protects mice from pulmonary fibrosis. The text does not clearly state how many people were studied.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study combining cell-culture experiments, experiments in normal (wild-type) and MCU-deficient mice, and measurements on alveolar macrophages obtained by bronchoalveolar lavage from normal participants and patients with asbestosis
• Who was studied: The human subjects were normal participants (aged 18–55, lifetime nonsmokers, no chronic disease) and patients with asbestosis (current nonsmokers, restrictive lung function, interstitial fibrosis on chest CT), studied at the University of Alabama at Birmingham. The total number of people is not stated; figure legends give n = 4 to 6 per measurement. The mice were wild-type and MCU+/- littermates aged 6–12 weeks, with equal numbers of males and females. The cell lines were human THP-1 monocytes and mouse MH-S alveolar macrophages.
• Exposure: Libby amphibole asbestos or chrysotile asbestos; the text does not say which type was used in each experiment. Mice received asbestos or titanium dioxide (TiO2, the comparison dust) into the windpipe and were studied after 21 days. The dose is printed as "125 mg", which may be scanning damage.
• Main results:
  • Alveolar macrophage mitochondria from patients with asbestosis showed more MCU than those from normal participants, and greater mitochondrial calcium.
  • In cultured mouse macrophages, asbestos exposure increased mitochondrial calcium, and this increased further when MCU was overexpressed.
  • Lung-wash cells from asbestos-exposed wild-type mice had significantly higher mitochondrial calcium than cells from TiO2-exposed mice. Levels in MCU+/- mice were comparable to TiO2-exposed wild-type mice.
  • Asbestos exposure significantly increased mitochondrial hydrogen peroxide in macrophages compared with unexposed controls. This increase was inhibited by the MCU inhibitor Ru360.
  • Asbestos-exposed wild-type mice had a 4-fold increase in TGF-b1 gene expression in alveolar macrophages. No difference was detected in TiO2- or asbestos-exposed MCU+/- mice.
  • Alveolar macrophages from asbestos-exposed wild-type mice had significantly more mitochondrial ATP than those from TiO2-exposed wild-type mice. Levels in asbestos-exposed MCU+/- mice were similar to the TiO2-exposed wild-type mice.
  • In cultured macrophages, blocking ATP production with oligomycin markedly reduced active TGF-b1 below levels in empty-vector control cells.
  • At 21 days, asbestos-exposed wild-type mice had dense collagen deposition and distorted lung architecture, while MCU+/- mice had essentially normal lungs. This was confirmed by a collagen (hydroxyproline) assay; 7 mice per condition.
• The authors' conclusion: The authors concluded that patients with pulmonary fibrosis have increased mitochondrial calcium in alveolar macrophages, and that MCU deficiency protects mice from pulmonary fibrosis.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Asbestosis.

Medical terms in this study, explained in our Lexicon: Macrophage, Fibrosis, Environmental Exposure, Asbestos Exposure, Oxidative Stress, Alveolar Macrophage, Reactive Oxygen Species (ROS), Pulmonary Fibrosis.

Related studies

• Cu,Zn-Superoxide Dismutase-Mediated Redox Regulation of Jumonji Domain Containing 3 Modulates Macrophage Polarization and Pulmonary Fibrosis — C. He, J.L. Larson-Casey, et al. (2016)
• NOX4 modulates macrophage phenotype and mitochondrial biogenesis in asbestosis — C. He, J.L. Larson-Casey, et al. (2019)
• Asbestos-induced disruption of calcium homeostasis induces endoplasmic reticulum stress in macrophages — A.J. Ryan, J.L. Larson-Casey, et al. (2014)
• NOX4 regulates macrophage apoptosis resistance to induce fibrotic progression — J.L. Larson-Casey, L. Gu, et al. (2021)
• Rac1-mediated mitochondrial H2O2 generation regulates MMP-9 gene expression in macrophages via inhibition of SP-1 and AP-1 — S. Murthy, A. Ryan, et al. (2010)
• Environmental mutagens induced transversions but not transitions in regulatory region of mitochondrial DNA — M.A. Partridge, S.X. Huang, et al. (2009)

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