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Mechanisms triggering the recruitment of mast cell progenitors to the lung and regulation of mast cell degranulation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mast cells stem from the bone marrow and migrate via the blood as mast cell progenitors. Upon arrival in peripheral tissues, they develop into mast cells. These rare immune cells have numerous granules that contain large amounts of pro-inflammatory mediators. Mast cells accumulate at certain sites in the asthmatic lung, and once activated they release mediators that are thought to induce symptoms. In mouse models of allergic airway inflammation, the increase in lung mast cells in asthma can be mimicked and is mainly caused by the recruitment of mast cell progenitors to the lung. However, whether other types of lung inflammation stimulate the recruitment of mast cell progenitors to the lung was unknown until now.

Here, using a murine model of influenza A virus infection, this type of virus was demonstrated to trigger an extensive recruitment of mast cell progenitors to the lung, most likely through the induction of VCAM-1 expression in the lung endothelium. Thereafter, some influenza-induced mast cell progenitors developed into an intermediate mast cell stage before they matured into mast cells. However, upon the resolution of inflammation, the mast cells that accumulated in the lung upon influenza infection were gradually lost.

Because the recruitment of mast cell progenitors started early after influenza infection, the role of innate immune signals in inducing the recruitment of mast cell progenitors was addressed. The intranasal administration of either Poly I:C or IL-33 was sufficient to induce an increase in lung mast cell progenitors in a TLR3- or ST2-dependent fashion. However, the influenza-induced recruitment of mast cell progenitors to the lung occurred independently of TLR3 and ST2.

VAAT/SLC10A4 is a member of the solute carrier family of proteins that is expressed in nerve cells and mast cells. In this study, murine VAAT was localized to mast cell granules and regulated the IgE/antigen-mediated release of granule-associated mediators and ATP. However, the absence of VAAT did not affect IgE/antigen-mediated de novo synthesis of cytokines and lipid mediators. Additionally, mice lacking VAAT had attenuated passive cutaneous anaphylaxis reactions and scratched less frequently in response to compound 48/80 injections, suggesting that VAAT regulates reactions for which mast cells are implicated in vivo.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1274
Keyword [en]
Mast cells, Mast cell progenitors, Recruitment, Lung, Virus, Influenza, Innate immunity, Poly I:C, IL-33, VAAT, SLC10A4, Degranulation
National Category
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-306115ISBN: 978-91-554-9746-0OAI: oai:DiVA.org:uu-306115DiVA: diva2:1040930
Public defence
2016-12-15, C8:301, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-11-23 Created: 2016-10-24 Last updated: 2016-11-28
List of papers
1. Influenza infection in mice induces the accumulation of lung mast cells through the recruitment and maturation of mast cell progenitors
Open this publication in new window or tab >>Influenza infection in mice induces the accumulation of lung mast cells through the recruitment and maturation of mast cell progenitors
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(English)Manuscript (preprint) (Other academic)
National Category
Immunology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-306111 (URN)
Available from: 2016-10-31 Created: 2016-10-24 Last updated: 2016-10-31
2. Stimulation of TLR3 or ST2 triggers an increase in the number of mast cell progenitors in the lung
Open this publication in new window or tab >>Stimulation of TLR3 or ST2 triggers an increase in the number of mast cell progenitors in the lung
(English)Manuscript (preprint) (Other academic)
National Category
Immunology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-306112 (URN)
Available from: 2016-10-31 Created: 2016-10-24 Last updated: 2016-10-31
3. VAAT regulates IgE-mediated mast cell degranulation in vitro and mast cell-mediated reactions in vivo
Open this publication in new window or tab >>VAAT regulates IgE-mediated mast cell degranulation in vitro and mast cell-mediated reactions in vivo
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(English)Manuscript (preprint) (Other academic)
National Category
Immunology Immunology in the medical area Neurosciences
Identifiers
urn:nbn:se:uu:diva-306114 (URN)
Available from: 2016-10-31 Created: 2016-10-24 Last updated: 2016-10-31

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Zarnegar, Behdad
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