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Selective Inhibition of IgG-Mediated Phagocytosis in Gelsolin-Deficient Murine Neutrophils
Divison of Infectious Diseases, University of Geneva, Switzerland.
Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
European Molecular Biology Laboratory Mouse Biology Program, Monterotondo, Italy.
Vise andre og tillknytning
2000 (engelsk)Inngår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 165, nr 5, s. 2451-2457Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Phagocytosis and the microbicidal functions of neutrophils require dynamic changes of the actin cytoskeleton. We have investigated the role of gelsolin, a calcium-dependent actin severing and capping protein, in peripheral blood neutrophils from gelsolin-null (Gsn) mice. The phagocytosis of complement opsonized yeast was only minimally affected. In contrast, phagocytosis of IgG-opsonized yeast was reduced close to background level in Gsn neutrophils. Thus, gelsolin is essential for efficient IgG- but not complement-mediated phagocytosis. Furthermore, attachment of IgG-opsonized yeast to Gsn neutrophils was reduced (∼50%) but not to the same extent as ingestion (∼73%). This was not due to reduced surface expression of the Fcγ-receptor or its lateral mobility. This suggests that attachment and ingestion of IgG-opsonized yeast by murine neutrophils are actin-dependent and gelsolin is important for both steps in phagocytosis. We also investigated granule exocytosis and several steps in phagosome processing, namely the formation of actin around the phagosome, translocation of granules, and activation of the NADPH-oxidase. All these functions were normal in Gsn neutrophils. Thus, the role of gelsolin is specific for IgG-mediated phagocytosis. Our data suggest that gelsolin is part of the molecular machinery that distinguishes complement and IgG-mediated phagocytosis. The latter requires a more dynamic reorganization of the cytoskeleton.

sted, utgiver, år, opplag, sider
2000. Vol. 165, nr 5, s. 2451-2457
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-49420PubMedID: 10946270OAI: oai:DiVA.org:liu-49420DiVA, id: diva2:270316
Tilgjengelig fra: 2009-10-11 Laget: 2009-10-11 Sist oppdatert: 2017-12-12bibliografisk kontrollert
Inngår i avhandling
1. The role of calcium and calcium-regulated proteins in neutrophil phagocytosis
Åpne denne publikasjonen i ny fane eller vindu >>The role of calcium and calcium-regulated proteins in neutrophil phagocytosis
2000 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Neutrophil phagocytosis is an essential component of the innate immunity against invading pathogens. The two types of phagocytosis that are investigated in detail are IgG- and C3bi-mediated phagocytosis. Although the two types are controlled differently, they share the same driving force - reorganisation of the actin cytoskeleton. Subcellular elevations of intracellular free calcium concentration ([Ca2+]1), are critical for this kind of functional response within the neutrophils.

The aim of this study was to try to understand how calcium and certain calciumregulated proteins control phagocytosis in neutrophils, especially the remodelling of the actin cytoskeleton during pseudopod fonnation and the regulation of phagolysosome fusion.

By immunofluorescence staining (IF) and confocal microscopy, we analysed the distribution of Ca2+ stores using antibodies against Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase (SERCA2) and calreticulin, during phagocytosis. The results showed a distinct accumulation of Ca2+ stores around phagosomes and pseudopods. This accumulation is coherent with a local Ca2+ rise seen in the area of phagocytosis and provides a model for how this localised [Ca2+]i is regulated in neutrophils. To further investigate if inositol 1,4,5-trisphosphate (IP3)-sensitive Ca2+ stores are involved, we analysed the subcellular distribution of IP3-receptors (IP3Rs), which are located on the ci+ stores. The IP3Rs translocated in a similar manner as did SERCA2 and calreticulin, indicating that the IP3-sensitive Ca2+ stores are involved.

During phagocytosis, an accumulation of phospholipid- and calcium-binding proteins, annexins, can be seen in the periphagosomal area. Several studies have demonstrated that certain annexins promote Ca2+-dependent contact between phospholipid vesicles and/or isolated neutrophil-specific granule membranes. This suggests that annexins, apart from being involved in vesicle aggregation and fusion, participate together with filamentous actin (F-actin) in phagolysosome formation, by establishing a connection between the phagosomal membrane and granule membranes prior to fusion. A prerequisite for phagolysosome fusion is the elimination of F-actin around the phagosomes to facilitate the membrane contact between lysosomes and phagosomes. We have, therefore, investigated the role of gelsolin, which is a protein that severs Factin by binding to the barbed ends, and thereby inhibits further polymerisation. The results show that both annexin I and Ill, and gelsolin translocates to the area of phagocytosis, in a Ca2+ -independent manner, where they eo-localise with F-actin.

sted, utgiver, år, opplag, sider
Linköping: Linköpings universitet, 2000. s. 40
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 619
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-28584 (URN)13738 (Lokal ID)91-7219-576-2 (ISBN)13738 (Arkivnummer)13738 (OAI)
Disputas
2000-03-17, Berzeliussalen, Universitetssjukhuset, Linköping, 09:00 (svensk)
Opponent
Tilgjengelig fra: 2009-10-09 Laget: 2009-10-09 Sist oppdatert: 2012-08-02bibliografisk kontrollert

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