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Lysosomotropic challenge of mast cells causes intra-granular reactive oxygen species production
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2019 (English)In: CELL DEATH DISCOVERY, ISSN 2058-7716, Vol. 5, article id 95Article in journal (Refereed) Published
Abstract [en]

Mast cells contribute to the pathology of allergic and other disorders. Strategies to interfere with harmful mast cell-related activities are therefore warranted. Previously we established a principle for inducing selective apoptosis of mast cells, by the use of lysosomotropic agents that cause secretory granule permeabilization, leading to production of reactive oxygen species (ROS). However, the mechanism of ROS production has not been known. Here we addressed this issue. Live microscopy analysis showed that the secretory granules comprise major subcellular compartments for ROS production in response to mefloquine. As further signs for the primary involvement of secretory granules, both ROS production and cell death was blunted in mast cells lacking serglycin, a secretory granule-restricted proteoglycan. Inhibition of granule acidification caused an essentially complete blockade of granule permeabilization, ROS production and cell death in response to mefloquine. ROS production was also attenuated in the presence of an iron chelator, and after inhibition of either granzyme B or the ERK1/2 MAP kinase signaling pathway. Together, our findings reveal that the mast cell secretory granules constitute major sites for ROS production in mast cells subjected to lysosomotropic challenge. Moreover, this study reveals a central role for granule acidification in ROS generation and the pro-apoptotic response triggered downstream of secretory granule permeabilization.

Place, publisher, year, edition, pages
2019. Vol. 5, article id 95
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-387281DOI: 10.1038/s41420-019-0177-3ISI: 000468005600001PubMedID: 31123601OAI: oai:DiVA.org:uu-387281DiVA, id: diva2:1329324
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationAvailable from: 2019-06-24 Created: 2019-06-24 Last updated: 2020-01-13Bibliographically approved
In thesis
1. Induction of Mast Cell Apoptosis via Granule Permeabilization: A Novel Approach to Target Mast Cells
Open this publication in new window or tab >>Induction of Mast Cell Apoptosis via Granule Permeabilization: A Novel Approach to Target Mast Cells
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mast cells are densely granulated tissue-resident immune cells that play an important role in orchestrating inflammatory responses. Dysregulated increases in the numbers and activation status of mast cells can have deleterious consequences for the body in various inflammatory diseases. Mast cells are best-known for their detrimental roles in allergic diseases, e.g., asthma. Thus, strategies that target mast cells and their harmful activities in such pathological conditions are potentially attractive therapeutic options. An efficient strategy to accomplish a full blockade of the harmful events mediated by various mast cell mediators is to locally eliminate mast cell populations altogether by inducing their apoptosis.

Using in vitro-cultured mast cells, we identified that mefloquine, an antimalarial drug with lysosomotropic activity, causes permeabilization of secretory granules, increased production of reactive oxygen species (ROS), release of granule-localized proteases into the cytosol and apoptotic cell death (Paper I). Moreover, intraperitoneal injections of mefloquine in mice resulted in a reduced peritoneal mast cell population in vivo.

To evaluate the possibility of using lysosomotropic agents for selectively depleting human lung mast cells by induction of apoptosis, human lung specimens were used. Exposure of either intact human lung tissue, purified lung mast cells or mixed populations of lung cells to mefloquine revealed that human lung mast cells are highly susceptible to ROS-induced apoptosis in this setting. In contrast, other cell populations of the lung were largely refractory (Paper II).

Lastly, in an attempt to gain a deeper insight into the mechanism underlying ROS production and the downstream events in response to lysosomotropic challenge, we identified that the mast cell secretory granules comprise major subcellular compartments for ROS production in response to mefloquine (Paper III). Lysosomal iron, granzyme B and the ERK1/2 MAP kinase signaling pathway were found to contribute to production of ROS in response to mefloquine. Furthermore, granule acidification was shown to be essential for mefloquine-mediated effects in mast cells, i.e., granule permeabilization, ROS production and cell death. Collectively, the present thesis introduces the possibility of inducing selective mast cell apoptosis via granule permeabilization as a novel strategy to target mast cells. Thus, this strategy has a potential to be used therapeutically to ameliorate mast cell-mediated detrimental effects in inflammatory diseases, such as asthma.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. p. 68
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1628
Keywords
Mast cells, Granules, Apoptosis, Reactive oxygen species, ROS, Lysosomotropic agents, Mefloquine
National Category
Immunology Biochemistry and Molecular Biology
Research subject
Immunology; Biochemistry
Identifiers
urn:nbn:se:uu:diva-402203 (URN)978-91-513-0848-7 (ISBN)
Public defence
2020-02-27, Room C8:301, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2020-02-06 Created: 2020-01-13 Last updated: 2020-02-06

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Paivandy, AidaEriksson, JensMelo, Fabio R.Sellin, Mikael E.Pejler, Gunnar

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