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Salomonsson, M., Malinovschi, A., Kalm-Stephens, P., Dahlin, J. S., Janson, C., Alving, K. & Hallgren, J. (2019). Circulating mast cell progenitors correlate with reduced lung function in allergic asthma. Clinical and Experimental Allergy, 49(6), 874-882
Open this publication in new window or tab >>Circulating mast cell progenitors correlate with reduced lung function in allergic asthma
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2019 (English)In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 49, no 6, p. 874-882Article in journal (Refereed) Published
Abstract [en]

Background

Studies using mouse models have revealed that mast cell progenitors are recruited from the blood circulation to the lung during acute allergic airway inflammation. The discovery of a corresponding human mast cell progenitor population in the blood has enabled to study the relation of circulating mast cell progenitors in clinical settings.

Objectives

To explore the possible association between the frequency of mast cell progenitors in the blood circulation and allergic asthma, we assessed the relation of this recently identified cell population with asthma outcomes and inflammatory mediators in allergic asthmatic patients and controls.

Methods

Blood samples were obtained, and spirometry was performed on 38 well‐controlled allergic asthmatic patients and 29 controls. The frequency of blood mast cell progenitors, total serum IgE and 180 inflammation‐ and immune‐related plasma proteins were quantified.

Results

Allergic asthmatic patients and controls had a similar mean frequency of blood mast cell progenitors, but the frequency was higher in allergic asthmatic patients with reduced FEV1 and PEF (% of predicted) as well as in women. The level of fibroblast growth factor 21 (FGF‐21) correlated positively with the frequency of mast cell progenitors, independent of age and gender, and negatively with lung function. The expression of FcεRI on mast cell progenitors was higher in allergic asthmatic patients and correlated positively with the level of total IgE in the controls but not in the asthmatic patients.

Conclusion

Elevated levels of circulating mast cell progenitors are related to reduced lung function, female gender and high levels of FGF‐21 in young adults with allergic asthma.

Keywords
allergic asthma, asthma, lung function, mast cell progenitors, mast cells
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-379233 (URN)10.1111/cea.13388 (DOI)000475694600015 ()30892731 (PubMedID)
Funder
Swedish Heart Lung Foundation, 20150379Swedish Asthma and Allergy Association, F2016-0045VinnovaSwedish Research Council, 2014-03293Swedish Research Council, 2016-00803Swedish Foundation for Strategic Research , RB13-0196Swedish Heart Lung Foundation, 20160618
Available from: 2019-03-26 Created: 2019-03-26 Last updated: 2019-09-20Bibliographically approved
Mendez-Enriquez, E. & Hallgren, J. (2019). Mast Cells and Their Progenitors in Allergic Asthma. Frontiers in Immunology, 10, Article ID 821.
Open this publication in new window or tab >>Mast Cells and Their Progenitors in Allergic Asthma
2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 821Article, review/survey (Refereed) Published
Abstract [en]

Mast cells and their mediators have been implicated in the pathogenesis of asthma and allergy for decades. Allergic asthma is a complex chronic lung disease in which several different immune cells, genetic factors and environmental exposures influence the pathology. Mast cells are key players in the asthmatic response through secretion of a multitude of mediators with pro-inflammatory and airway-constrictive effects. Well-known mast cell mediators, such as histamine and bioactive lipids are responsible for many of the physiological effects observed in the acute phase of allergic reactions. The accumulation of mast cells at particular sites of the allergic lung is likely relevant to the asthma phenotype, severity and progression. Mast cells located in different compartments in the lung and airways have different characteristics and express different mediators. According to in vivo experiments in mice, lung mast cells develop from mast cell progenitors induced by inflammatory stimuli to migrate to the airways. Human mast cell progenitors have been identified in the blood circulation. A high frequency of circulating human mast cell progenitors may reflect ongoing pathological changes in the allergic lung. In allergic asthma, mast cells become activated mainly via IgE-mediated crosslinking of the high affinity receptor for IgE (Fc epsilon RI) with allergens. However, mast cells can also be activated by numerous other stimuli e.g. toll-like receptors and MAS-related G protein-coupled receptor X2. In this review, we summarize research with implications on the role and development of mast cells and their progenitors in allergic asthma and cover selected activation pathways and mast cell mediators that have been implicated in the pathogenesis. The review places an emphasis on describing mechanisms identified using in vivo mouse models and data obtained by analysis of clinical samples.

Keywords
mast cell, mast cell progenitors, allergic asthma, mast cell development, mast cell activation
National Category
Respiratory Medicine and Allergy Immunology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-387530 (URN)10.3389/fimmu.2019.00821 (DOI)000469431500001 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Heart Lung FoundationKing Gustaf V Jubilee Fund
Available from: 2019-06-24 Created: 2019-06-24 Last updated: 2019-06-24Bibliographically approved
Zarnegar, B., Westin, A., Evangelidou, S. & Hallgren, J. (2018). Innate Immunity Induces the Accumulation of Lung Mast Cells During Influenza Infection. Frontiers in Immunology, 9, Article ID 2288.
Open this publication in new window or tab >>Innate Immunity Induces the Accumulation of Lung Mast Cells During Influenza Infection
2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2288Article in journal (Refereed) Published
Abstract [en]

Mast cells release disease-causing mediators and accumulate in the lung of asthmatics. The most common cause of exacerbations of asthma is respiratory virus infections such as influenza. Recently, we demonstrated that influenza infection in mice triggers the recruitment of mast cell progenitors to the lung. This process starts early after infection and leads to the accumulation of mast cells. Previous studies showed that an adaptive immune response was required to trigger the recruitment of mast cell progenitors to the lung in a mouse model of allergic lung inflammation. Therefore, we set out to determine whether an adaptive immune response against the virus is needed to cause the influenza-induced recruitment of mast cell progenitors to the lung. We found that influenza-induced recruitment of mast cell progenitors to the lung was intact in Rag2(-/-) mice and mice depleted of CD4(+) cells, implicating the involvement of innate immune signals in this process. Seven weeks after the primary infection, the influenza-exposed mice harbored more lung mast cells than unexposed mice. As innate immunity was implicated in stimulating the recruitment process, several compounds known to trigger innate immune responses were administrated intranasally to test their ability to cause an increase in lung mast cell progenitors. Poly I:C, a synthetic analog of viral dsRNA, induced a TLR3-dependent increase in lung mast cell progenitors. In addition, IL-33 induced an ST2-dependent increase in lung mast cell progenitors. In contrast, the influenza-induced recruitment of mast cell progenitors to the lung occurred independently of either TLR3 or ST2, as demonstrated using Tlr3(-/-) or Il1rl1(-/-) mice. Furthermore, neutralization of IL-33 in Tlr3(-/-) mice could not abrogate the influenza-induced influx of mast cell progenitors to the lung. These results suggest that other innate receptor(s) contribute to mount the influx of mast cell progenitors to the lung upon influenza infection. Our study establishes that mast cell progenitors can be rapidly recruited to the lung by innate immune signals. This indicates that during life various innate stimuli of the respiratory tract trigger increases in the mast cell population within the lung. The expanded mast cell population may contribute to the exacerbations of symptoms which occurs when asthmatics are exposed to respiratory infections.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
mast cells, influenza, TLR3, ST2, mouse model
National Category
Immunology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-367387 (URN)10.3389/fimmu.2018.02288 (DOI)000446346900001 ()
Funder
Swedish Research CouncilThe Royal Swedish Academy of Sciences
Available from: 2018-12-04 Created: 2018-12-04 Last updated: 2018-12-04Bibliographically approved
Zarnegar, B., Mendez-Enriquez, E., Westin, A., Söderberg, C., Dahlin, J. S., Grönvik, K.-O. & Hallgren, J. (2017). Influenza Infection in Mice Induces Accumulation of Lung Mast Cells through the Recruitment and Maturation of Mast Cell Progenitors. Frontiers in Immunology, 8, Article ID 310.
Open this publication in new window or tab >>Influenza Infection in Mice Induces Accumulation of Lung Mast Cells through the Recruitment and Maturation of Mast Cell Progenitors
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2017 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 310Article in journal (Refereed) Published
Abstract [en]

Mast cells (MCs) are powerful immune cells that mature in the peripheral tissues from bone marrow (BM)-derived mast cell progenitors (MCp). Accumulation of MCs in lung compartments where they are normally absent is thought to enhance symptoms in asthma. The enrichment of lung MCs is also observed in mice subjected to models of allergic airway inflammation. However, whether other types of lung inflammation trigger increased number of MCp, which give rise to MCs, is unknown. Here, mouse-adapted H1N1 influenza A was used as a model of respiratory virus infection. Intranasal administration of the virus induced expression of VCAM-1 on the lung vascular endothelium and an extensive increase in integrin beta 7(hi) lung MCp. Experiments were performed to distinguish whether the influenza-induced increase in the number of lung MCp was triggered mainly by recruitment or in situ cell proliferation. A similar proportion of lung MCp from influenza-infected and PBS control mice were found to be in a proliferative state. Furthermore, BM chimeric mice were used in which the possibility of influenza-induced in situ cell proliferation of host MCp was prevented. Influenza infection in the chimeric mice induced a similar number of lung MCp as in normal mice. These experiments demonstrated that recruitment of MCp to the lung is the major mechanism behind the influenza-induced increase in lung MCp. Fifteen days post-infection, the influenza infection had elicited an immature MC population expressing intermediate levels of integrin beta 7, which was absent in controls. At the same time point, an increased number of toluidine blue(+) MCs was detected in the upper central airways. When the inflammation was resolved, the MCs that accumulated in the lung upon influenza infection were gradually lost. In summary, our study reveals that influenza infection induces a transient accumulation of lung MCs through the recruitment and maturation of MCp. We speculate that temporary augmented numbers of lung MCs are a cause behind virus-induced exacerbations of MC-related lung diseases such as asthma.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2017
Keywords
mast cells, mast cell progenitors, recruitment, influenza, virus, lung
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-320203 (URN)10.3389/fimmu.2017.00310 (DOI)000397141600002 ()28382037 (PubMedID)
Funder
The Royal Swedish Academy of SciencesSwedish Research Council
Available from: 2017-04-18 Created: 2017-04-18 Last updated: 2018-11-08Bibliographically approved
Pettersson, H., Zarnegar, B., Westin, A., Persson, V., Peuckert, C., Jonsson, J., . . . Kullander, K. (2017). SLC10A4 regulates IgE-mediated mast cell degranulation in vitro and mast cell-mediated reactions in vivo. Scientific Reports, 7, Article ID 1085.
Open this publication in new window or tab >>SLC10A4 regulates IgE-mediated mast cell degranulation in vitro and mast cell-mediated reactions in vivo
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 1085Article in journal (Refereed) Published
Abstract [en]

Mast cells act as sensors in innate immunity and as effector cells in adaptive immune reactions. Here we demonstrate that SLC10A4, also referred to as the vesicular aminergic-associated transporter, VAAT, modifies mast cell degranulation. Strikingly, Slc10a4(-/-) bone marrow-derived mast cells (BMMCs) had a significant reduction in the release of granule-associated mediators in response to IgE/antigen-mediated activation, whereas the in vitro development of mast cells, the storage of the granule-associated enzyme mouse mast cell protease 6 (mMCP-6), and the release of prostaglandin D2 and IL-6 were normal. Slc10a4-deficient mice had a strongly reduced passive cutaneous anaphylaxis reaction and a less intense itching behaviour in response to the mast cell degranulator 48/80. Live imaging of the IgE/antigen-mediated activation showed decreased degranulation and that ATP was retained to a higher degree in mast cell granules lacking SLC10A4. Furthermore, ATP was reduced by two thirds in Slc10a4(-/-) BMMCs supernatants in response to IgE/antigen. We speculate that SLC10A4 affects the amount of granule-associated ATP upon IgE/antigen-induced mast cell activation, which affect the release of granule-associated mast cell mediators. In summary, SLC10A4 acts as a regulator of degranulation in vitro and of mast cell-related reactions in vivo.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-322797 (URN)10.1038/s41598-017-01121-8 (DOI)000400048500001 ()28439090 (PubMedID)
Funder
Swedish Research Council
Available from: 2017-06-14 Created: 2017-06-14 Last updated: 2018-01-13Bibliographically approved
Klein, O., Ngo-Nyekel, F., Stefanache, T., Torres, R., Salomonsson, M., Hallgren, J., . . . Maurer, M. (2016). Identification of Biological and Pharmaceutical Mast Cell- and Basophil-Related Targets [Letter to the editor]. Scandinavian Journal of Immunology, 83(6), 465-472
Open this publication in new window or tab >>Identification of Biological and Pharmaceutical Mast Cell- and Basophil-Related Targets
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2016 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 83, no 6, p. 465-472Article in journal, Letter (Refereed) Published
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-301138 (URN)10.1111/sji.12436 (DOI)000379922400009 ()27028428 (PubMedID)
Available from: 2016-08-23 Created: 2016-08-18 Last updated: 2018-01-10Bibliographically approved
Dahlin, J. S., Malinovschi, A., Öhrvik, H., Sandelin, M., Janson, C., Alving, K. & Hallgren, J. (2016). Lineage- CD34hi CD117int/hi FcϵRI+ cells in human blood constitute a rare population of mast cell progenitors. Blood, 127(4), 383-391
Open this publication in new window or tab >>Lineage- CD34hi CD117int/hi FcϵRI+ cells in human blood constitute a rare population of mast cell progenitors
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2016 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 127, no 4, p. 383-391Article in journal (Refereed) Published
Abstract [en]

Mast cells are rare tissue-resident immune cells that are involved in allergic reactions, and their numbers are increased in the lungs of asthmatics. Murine lung mast cells arise from committed bone marrow-derived progenitors that enter the blood circulation, migrate through the pulmonary endothelium, and mature in the tissue. In humans, mast cells can be cultured from multipotent CD34(+) progenitor cells. However, a population of distinct precursor cells that give rise to mast cells has remained undiscovered. To our knowledge, this is the first report of human lineage(-) CD34(hi) CD117(int/hi) FcϵRI(+) progenitor cells, which represented only 0.0053% of the isolated blood cells in healthy individuals. These cells expressed integrin β7 and developed a mast cell-like phenotype, although with a slow cell division capacity in vitro. Isolated lineage(-) CD34(hi) CD117(int/hi) FcϵRI(+) blood cells had an immature mast cell-like appearance and expressed high levels of many mast cell-related genes as compared with human blood basophils in whole-transcriptome microarray analyses. Furthermore, serglycin, tryptase, and carboxypeptidase A mRNA transcripts were detected by quantitative RT-PCR. Altogether, we propose that the lineage(-) CD34(hi) CD117(int/hi) FcϵRI(+) blood cells are closely related to human tissue mast cells and likely constitute an immediate precursor population, which can give rise to predominantly mast cells. Furthermore, asthmatics with reduced lung function had a higher frequency of lineage(-) CD34(hi) CD117(int/hi) FcϵRI(+) blood mast cell progenitors than asthmatics with normal lung function.

National Category
Medical and Health Sciences Hematology
Identifiers
urn:nbn:se:uu:diva-270369 (URN)10.1182/blood-2015-06-650648 (DOI)000369288300007 ()26626992 (PubMedID)
Available from: 2015-12-27 Created: 2015-12-27 Last updated: 2017-12-01
Dahlin, J. S., Ding, Z. & Hallgren, J. (2015). Distinguishing Mast Cell Progenitors from Mature Mast Cells in Mice. Stem Cells and Development, 24(14), 1703-1711
Open this publication in new window or tab >>Distinguishing Mast Cell Progenitors from Mature Mast Cells in Mice
2015 (English)In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 24, no 14, p. 1703-1711Article in journal (Refereed) Published
Abstract [en]

Mast cells originate from the bone marrow and develop into c-kit(+) FcRI(+) cells. Both mast cell progenitors (MCp) and mature mast cells express these cell surface markers, and ways validated to distinguish between the two maturation forms with flow cytometry have been lacking. Here, we show that primary peritoneal MCp from naive mice expressed high levels of integrin 7 and had a low side scatter (SSC) light profile; whereas mature mast cells expressed lower levels of integrin 7 and had a high SSC light profile. The maturation statuses of the cells were confirmed using three main strategies: (1) MCp, but not mature mast cells, were shown to be depleted by sublethal whole-body -irradiation. (2) The MCp were small and immature in terms of granule formation, whereas the mature mast cells were larger and had fully developed metachromatic granules. (3) The MCp had fewer transcripts of mast cell-specific proteases and the enzyme responsible for sulfation of heparin than mature mast cells. Moreover, isolated peritoneal MCp gave rise to mast cells when cultured in vitro. To summarize, we have defined MCp and mature mast cells in naive mice by flow cytometry. Using this strategy, mast cell maturation can be studied in vivo.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-265939 (URN)10.1089/scd.2014.0553 (DOI)000362083800007 ()25744159 (PubMedID)
Funder
The Royal Swedish Academy of SciencesSwedish Research Council
Available from: 2015-11-04 Created: 2015-11-04 Last updated: 2018-01-10Bibliographically approved
Dahlin, J. S. & Hallgren, J. (2015). Mast cell progenitors: Origin, development and migration to tissues. Molecular Immunology, 63(1), 9-17
Open this publication in new window or tab >>Mast cell progenitors: Origin, development and migration to tissues
2015 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 63, no 1, p. 9-17Article, review/survey (Refereed) Published
Abstract [en]

Mast cells in tissues are developed from mast cell progenitors emerging from the bone marrow in a process highly regulated by transcription factors. Through the advancement of the multicolor flow cytometry technique, the mast cell progenitor population in the mouse has been characterized in terms of surface markers. However, only cell populations with enriched mast cell capability have been described in human. In naïve mice, the peripheral tissues have a constitutive pool of mast cell progenitors. Upon infections in the gut and in allergic inflammation in the lung, the local mast cell progenitor numbers increase tremendously. This review focuses on the origin and development of mast cell progenitors. Furthermore, the evidences for cells and molecules that govern the migration of these cells in mice in vivo are described.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-234041 (URN)10.1016/j.molimm.2014.01.018 (DOI)000343846900003 ()24598075 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung Foundation
Available from: 2014-10-13 Created: 2014-10-13 Last updated: 2018-01-11Bibliographically approved
Zarnegar, B., Dahlin, J., Westin, A. & Hallgren Martinsson, J. (2014). Does Cell Proliferation Contribute to the OVA-Induced Increase of Lung Mast Cell Progenitors in a Mouse Asthma Model?. Paper presented at 42nd Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), JUN 11-14, 2014, Reykjavik, ICELAND. Scandinavian Journal of Immunology, 79(6), 463-463
Open this publication in new window or tab >>Does Cell Proliferation Contribute to the OVA-Induced Increase of Lung Mast Cell Progenitors in a Mouse Asthma Model?
2014 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 463-463Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-228901 (URN)000337588500097 ()
Conference
42nd Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), JUN 11-14, 2014, Reykjavik, ICELAND
Available from: 2014-07-22 Created: 2014-07-22 Last updated: 2018-01-11Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-3685-5364

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