Mitochondrial Calcium Uptake Is Instrumental to Alternative Macrophage Polarization and Phagocytic Activity
Macrophages are highly plastic and dynamic cells that exert much of their function through phagocytosis. Phagocytosis depends on a coordinated, finely tuned, and compartmentalized regulation of calcium concentrations. We examined the role of mitochondrial calcium uptake and mitochondrial calcium uni...
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doaj-cd1bc8e15f014bdbb82a3d6c877c1f082020-11-25T02:01:01ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-10-012019496610.3390/ijms20194966ijms20194966Mitochondrial Calcium Uptake Is Instrumental to Alternative Macrophage Polarization and Phagocytic ActivitySerena Tedesco0Valentina Scattolini1Mattia Albiero2Mario Bortolozzi3Angelo Avogaro4Andrea Cignarella5Gian Paolo Fadini6Department of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, ItalyDepartment of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, ItalyDepartment of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, ItalyVeneto Institute of Molecular Medicine, Via G. Orus 2, 35129 Padova, ItalyDepartment of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, ItalyDepartment of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, ItalyDepartment of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, ItalyMacrophages are highly plastic and dynamic cells that exert much of their function through phagocytosis. Phagocytosis depends on a coordinated, finely tuned, and compartmentalized regulation of calcium concentrations. We examined the role of mitochondrial calcium uptake and mitochondrial calcium uniporter (MCU) in macrophage polarization and function. In primary cultures of human monocyte-derived macrophages, calcium uptake in mitochondria was instrumental for alternative (M2) macrophage polarization. Mitochondrial calcium uniporter inhibition with KB-R7943 or MCU knockdown, which prevented mitochondrial calcium uptake, reduced M2 polarization, while not affecting classical (M1) polarization. Challenging macrophages with <i>E. coli</i> fragments induced spikes of mitochondrial calcium concentrations, which were prevented by MCU inhibition or silencing. In addition, mitochondria remodelled in M2 macrophages during phagocytosis, especially close to sites of <i>E. coli</i> internalization. Remarkably, inhibition or knockdown of MCU significantly reduced the phagocytic capacity of M2 macrophages. KB-R7943, which also inhibits the membrane sodium/calcium exchanger and Complex I, reduced mitochondria energization and cellular ATP levels, but such effects were not observed with MCU silencing. Therefore, phagocytosis inhibition by MCU knockdown depended on the impaired mitochondrial calcium buffering rather than changes in mitochondrial and cellular energy status. These data uncover a new role for MCU in alternative macrophage polarization and phagocytic activity.https://www.mdpi.com/1422-0067/20/19/4966macrophagephagocytosisinnate immunitysecond messengercalciummitochondria |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Serena Tedesco Valentina Scattolini Mattia Albiero Mario Bortolozzi Angelo Avogaro Andrea Cignarella Gian Paolo Fadini |
spellingShingle |
Serena Tedesco Valentina Scattolini Mattia Albiero Mario Bortolozzi Angelo Avogaro Andrea Cignarella Gian Paolo Fadini Mitochondrial Calcium Uptake Is Instrumental to Alternative Macrophage Polarization and Phagocytic Activity International Journal of Molecular Sciences macrophage phagocytosis innate immunity second messenger calcium mitochondria |
author_facet |
Serena Tedesco Valentina Scattolini Mattia Albiero Mario Bortolozzi Angelo Avogaro Andrea Cignarella Gian Paolo Fadini |
author_sort |
Serena Tedesco |
title |
Mitochondrial Calcium Uptake Is Instrumental to Alternative Macrophage Polarization and Phagocytic Activity |
title_short |
Mitochondrial Calcium Uptake Is Instrumental to Alternative Macrophage Polarization and Phagocytic Activity |
title_full |
Mitochondrial Calcium Uptake Is Instrumental to Alternative Macrophage Polarization and Phagocytic Activity |
title_fullStr |
Mitochondrial Calcium Uptake Is Instrumental to Alternative Macrophage Polarization and Phagocytic Activity |
title_full_unstemmed |
Mitochondrial Calcium Uptake Is Instrumental to Alternative Macrophage Polarization and Phagocytic Activity |
title_sort |
mitochondrial calcium uptake is instrumental to alternative macrophage polarization and phagocytic activity |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2019-10-01 |
description |
Macrophages are highly plastic and dynamic cells that exert much of their function through phagocytosis. Phagocytosis depends on a coordinated, finely tuned, and compartmentalized regulation of calcium concentrations. We examined the role of mitochondrial calcium uptake and mitochondrial calcium uniporter (MCU) in macrophage polarization and function. In primary cultures of human monocyte-derived macrophages, calcium uptake in mitochondria was instrumental for alternative (M2) macrophage polarization. Mitochondrial calcium uniporter inhibition with KB-R7943 or MCU knockdown, which prevented mitochondrial calcium uptake, reduced M2 polarization, while not affecting classical (M1) polarization. Challenging macrophages with <i>E. coli</i> fragments induced spikes of mitochondrial calcium concentrations, which were prevented by MCU inhibition or silencing. In addition, mitochondria remodelled in M2 macrophages during phagocytosis, especially close to sites of <i>E. coli</i> internalization. Remarkably, inhibition or knockdown of MCU significantly reduced the phagocytic capacity of M2 macrophages. KB-R7943, which also inhibits the membrane sodium/calcium exchanger and Complex I, reduced mitochondria energization and cellular ATP levels, but such effects were not observed with MCU silencing. Therefore, phagocytosis inhibition by MCU knockdown depended on the impaired mitochondrial calcium buffering rather than changes in mitochondrial and cellular energy status. These data uncover a new role for MCU in alternative macrophage polarization and phagocytic activity. |
topic |
macrophage phagocytosis innate immunity second messenger calcium mitochondria |
url |
https://www.mdpi.com/1422-0067/20/19/4966 |
work_keys_str_mv |
AT serenatedesco mitochondrialcalciumuptakeisinstrumentaltoalternativemacrophagepolarizationandphagocyticactivity AT valentinascattolini mitochondrialcalciumuptakeisinstrumentaltoalternativemacrophagepolarizationandphagocyticactivity AT mattiaalbiero mitochondrialcalciumuptakeisinstrumentaltoalternativemacrophagepolarizationandphagocyticactivity AT mariobortolozzi mitochondrialcalciumuptakeisinstrumentaltoalternativemacrophagepolarizationandphagocyticactivity AT angeloavogaro mitochondrialcalciumuptakeisinstrumentaltoalternativemacrophagepolarizationandphagocyticactivity AT andreacignarella mitochondrialcalciumuptakeisinstrumentaltoalternativemacrophagepolarizationandphagocyticactivity AT gianpaolofadini mitochondrialcalciumuptakeisinstrumentaltoalternativemacrophagepolarizationandphagocyticactivity |
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1724959346351144960 |