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Studies of SIRPα-mediated regulation of neutrophil functions
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neutrophil granulocytes constitute the front line of defense in the innate immune response to invading microorganisms, but can also contribute to development of inflammatory disease and tissue destruction following e.g. myocardial infarction or stroke. During inflammatory activation, neutrophils leave the blood, interact with extracellular matrix proteins, and migrate into tissues in response to chemotactic factors to phagocytose and kill infectious agents by using toxic granule contents and reactive oxygen metabolites. The functional neutrophil response relies on exocytosis of cytoplasmic granules, each containing membrane proteins, which are thereby mobilized to the plasma membrane. Specific programmed cell death (apoptotic) pathways regulate neutrophil homeostasis, where an inflammatory milieu can prolong the life span of neutrophils to several days, whereas non-activated neutrophils are committed to constitutive/spontaneous apoptosis within hours.

Signal regulatory protein alpha (SIRPα) is a surface glycoprotein with two intracellular immunoreceptor-tyrosine-based inhibitory motifs (ITIMs), which is highly expressed in neutrophils and other myeloid cells. In other cell types, SIRPα has been shown to regulate cellular functions such as cell migration and phagocytosis. The aim of the present thesis was to investigate neutrophil SIRPα expression in response to inflammatory activation or apoptosis, and how this receptor can regulate neutrophil adhesion and cell migration.

Neutrophils contain several subcellular granule compartments, including primary (azurophilic), secondary (specific), tertiary (gelatinase) granules, and a fourth compartment called secretory vesicles. In resting neutrophils, SIRPα was found to be present in the plasma membrane and in all types of granules except for the azurophilic granules. Stimulation with the bacterial peptide fMLF in vitro, or inflammatory activation in vivo, was found to rapidly mobilize SIRPα to the neutrophil cell surface. In mice expressing a mutated form of SIRPα, where the cytoplasmic signaling domain was deleted, we found an enhanced accumulation of neutrophils in the peritoneal cavity in a peritonitis model. These findings therefore suggest that an increased amount of SIRPα on the surface of activated neutrophils could serve to negatively fine-tune neutrophil accumulation in inflammation.

Neutrophil priming means that the cell becomes partially activated, in a way that facilitates subsequent full activation. One part of the priming process is a moderate exocytosis of granules, mostly the secretory vesicles, which increases the density of certain receptors on the cell surface. It also involves the activation of adhesion receptors called integrins. We found that TNFα-induced priming involved an increased accumulation of SIRPα on the cell surface. When comparing wild-type and SIRPα-mutant neutrophils, we found a strongly reduced TNFα-stimulated and β2 integrin-dependent adhesion of mutant neutrophils to type I collagen or fibrinogen. This adhesion defect resulted in a reduced adhesion-dependent activation of the respiratory burst and an increased chemotactic response of SIRPα-mutant neutrophils in vitro.

During neutrophil apoptosis, several receptors are known to be shed from the cell surface (e.g. CD16 and CD43). We found that also SIRPα is shed from the surface during spontaneous as well as Fas-induced apoptosis. The shedding mechanism was found to involve matrix metalloproteinase (MMP) activity, mostly that of MMP-3 and MMP-8.

In conclusion, neutrophil cell surface SIRPα expression is regulated during neutrophil activation and seems to play an important role in stimulating β2-integrin-dependent adhesion. This way, SIRPα can negatively fine-tune neutrophil migration and accumulation in inflammation. During apoptosis, SIRPα is shed from the cell surface, which may be one mechanism contributing to the well-known down-regulation in the adhesiveness of apoptotic neutrophils.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2014. , 55 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1630
Keyword [en]
neutrophils, SIRPα, inflammation, adhesion, chemotaxis, apoptosis
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-86744ISBN: 978-91-7459-808-7 (print)OAI: oai:DiVA.org:umu-86744DiVA: diva2:703469
Public defence
2014-03-28, Biologihuset, BiA201, Umeå universitet, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Funder
Swedish Research Council, 2012-2702
Available from: 2014-03-07 Created: 2014-03-06 Last updated: 2014-03-07Bibliographically approved
List of papers
1. Signal regulatory protein alpha is present in several neutrophil granule populations and is rapidly mobilized to the cell surface to negatively fine-tune neutrophil accumulation in inflammation
Open this publication in new window or tab >>Signal regulatory protein alpha is present in several neutrophil granule populations and is rapidly mobilized to the cell surface to negatively fine-tune neutrophil accumulation in inflammation
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2014 (English)In: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 6, no 4, 553-560 p.Article in journal (Refereed) Published
Abstract [en]

Signal regulatory protein alpha (SIRPα) is a cell surface glycoprotein with inhibitory functions, which may regulate neutrophil transmigration. SIRPα is mobilized to the neutrophil surface from specific granules, gelatinase granules, and secretory vesicles following inflammatory activation in vitro and in vivo. The lack of SIRPα signaling and the ability to upregulate SIRPα to the cell surface promote neutrophil accumulation during inflammation in vivo.

Keyword
Neutrophils, Inflammation, Signal regulatory protein alpha, Chemotactic factor, Skin window, Exudate
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-86668 (URN)10.1159/000357820 (DOI)000337655900013 ()24516072 (PubMedID)
Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2017-12-05Bibliographically approved
2. Signal regulatory protein alpha (SIRPα) negatively regulates neutrophil migration by stimulating β2 integrin-mediated adhesion
Open this publication in new window or tab >>Signal regulatory protein alpha (SIRPα) negatively regulates neutrophil migration by stimulating β2 integrin-mediated adhesion
(English)Manuscript (preprint) (Other academic)
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-86743 (URN)
Available from: 2014-03-06 Created: 2014-03-06 Last updated: 2014-03-07Bibliographically approved
3. Neutrophil apoptosis is associated with loss of signal regulatory protein alpha (SIRP alpha) from the cell surface
Open this publication in new window or tab >>Neutrophil apoptosis is associated with loss of signal regulatory protein alpha (SIRP alpha) from the cell surface
2013 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 93, no 3, 403-412 p.Article in journal (Refereed) Published
Abstract [en]

Cells of the innate immune system, including monocytes, macrophages, and neutrophils, play a major role in the development of inflammatory diseases. During inflammation, large numbers of neutrophils are recruited from the blood and subsequently undergo apoptosis, which involves changes in the cell surface expression of a number of receptors. Neutrophils express the Ig superfamily member, SIRP alpha, which is a receptor involved in regulating cell adhesion and migration. As apoptotic neutrophils down-regulate their capacity for adhesion and migration, we here investigated whether neutrophil expression of SIRP alpha was affected during apoptosis. We found that apoptotic neutrophils lost SIRP alpha from their cell surface with kinetics similar to the loss of CD16. The majority of neutrophils with reduced SIRP alpha also expressed PS on their surface, and the loss of the receptor was reduced proportional to the reduction of apoptosis by caspase inhibitors during Fas-induced apoptosis but less so during spontaneous apoptosis. Neutrophil loss of SIRP alpha or CD16 was inhibited by the protease inhibitor TAPI-2, as well as specific inhibitors of MMP3 or -8, suggesting that proteolytic mechanisms were involved. Finally, SIRP alpha was also found on smaller membrane vesicles released from the cells during apoptosis. Our data suggest that neutrophils reduce their SIRP alpha expression during apoptosis, which may be part of the functional down-regulation seen in apoptotic neutrophils. J. Leukoc. Biol. 93: 403-412; 2013.

Keyword
inflammation, proteolytic shedding, Fas, caspase, CD16
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-67799 (URN)10.1189/jlb.1110637 (DOI)000315579700010 ()
Available from: 2013-04-05 Created: 2013-04-03 Last updated: 2017-12-06Bibliographically approved

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