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Induction of Human Lung Mast Cell Apoptosis by Granule Permeabilization: A Novel Approach for Targeting Mast Cells
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 Sciences.ORCID iD: 0000-0002-0370-8819
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotherapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
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2017 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 1645Article in journal (Refereed) Published
Abstract [en]

Mast cells are implicated as detrimental players in inflammatory lung diseases, particularly asthma. Mast cells respond to activating stimuli by releasing a wide panel of pro-inflammatory compounds that can contribute profoundly to the pathology, and there is currently an unmet need for strategies that efficiently ameliorate harmful effects of mast cells under such conditions. Here, we sought to evaluate a novel concept for targeting human lung mast cells, by assessing the possibility of selectively depleting the lung mast cells by induction of apoptosis. For this purpose, we used lysosomotropic agents, i.e., compounds that are known to permeabilize the secretory granules of mast cells, thereby releasing the contents of the granules into the cytosol. Either intact human lung tissue, purified human lung mast cells or mixed populations of human lung cells were incubated with the lysosomotropic agents mefloquine or siramesine, followed by measurement of apoptosis, reactive oxygen species (ROS) production, and release of cytokines. We show that human lung mast cells were highly susceptible to apoptosis induced by this strategy, whereas other cell populations of the lung were largely refractory. Moreover, we demonstrate that apoptosis induced by this mode is dependent on the production of ROS and that the treatment of lung tissue with lysosomotropic agents causes a decrease in the release of pathogenic cytokines. We conclude that selective apoptosis of human lung mast cells can be accomplished by administration of lysosomotropic agents, thus introducing the possibility of using such drugs as novel therapeutics in the treatment of inflammatory lung disorders such as asthma.

Place, publisher, year, edition, pages
2017. Vol. 8, article id 1645
Keywords [en]
apoptosis, granules, lysosomotropic agents, mast cells, mefloquine
National Category
Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-339681DOI: 10.3389/fimmu.2017.01645ISI: 000416221900001PubMedID: 29230220OAI: oai:DiVA.org:uu-339681DiVA, id: diva2:1176492
Available from: 2018-01-22 Created: 2018-01-22 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, AidaSandelin, MartinIgelström, HelenaLandelius, PerJanson, ChristerMelo, Fabio R.Pejler, Gunnar

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