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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
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Cell Biology
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URN: urn:nbn:se:uu:diva-387281DOI: 10.1038/s41420-019-0177-3ISI: 000468005600001PubMedID: 31123601OAI: oai:DiVA.org:uu-387281DiVA, id: diva2:1329324
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Swedish Research CouncilKnut and Alice Wallenberg FoundationAvailable from: 2019-06-24 Created: 2019-06-24 Last updated: 2019-06-24Bibliographically approved

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