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- Blomgran, Robert,1975-Linköpings universitet,Medicinsk mikrobiologi,Hälsouniversitetet (author)
Microbe-induced apoptosis in phagocytic cells and its role in innate immunity
- BookEnglish2006
Publisher, publication year, extent ...
- Institutionen för molekylär och klinisk medicin,2006
- electronicrdacarrier
Numbers
- LIBRIS-ID:oai:DiVA.org:liu-7445
- ISBN:9185523119
- https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-7445URI
Supplementary language notes
- Language:English
- Summary in:English
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Series
- Linköping University Medical Dissertations,0345-0082 ;956
Notes
- Apoptosis, or programmed cell death, is a controlled process by which aged or damages cells are eliminated in multicellular organisms. Neutrophils, short-lived phagocytes of the innate immune system, are highly equipped effectors that can sense, locate, ingest and kill bacterial pathogens. Inflammatory mediators and the presence of bacterial products at the foci of infection regulate the function and life span of these cells. Modulation of neutrophil apoptosis and the subsequent clearance by scavenger cells, such as macrophages, is part of a balanced inflammatory process leading to resolution of inflammation. Many pathogens are capable of modulating host cell apoptosis, and thereby influence the progression of disease. Hence, this thesis was aiming at elucidating mechanisms involved in pathogen- and host-modulated apoptosis and its contribution to the inflammatory process.We found that different routes of bacterial entry, i.e. through invasion or by receptor-mediated phagocytosis, triggered different signaling pathways within phagocytes. Invasion of virulent Salmonella caused apoptosis, a process requiring activation of the Rho GTPases Rac1 and Cdc42. On the other hand, phagocytosis of the non-invasive Salmonella inhibited apoptosis despite similar intracellular survival as the invasive bacteria. Protection against phagocytosis-induced apoptosis was regulated by tyrosine- and PI3-kinase-dependent activation of AKT (also called PKB for protein kinase B). Furthermore, inhibiting the intraphagosomal production of reactive oxygen species (ROS) in neutrophils during phagocytosis of E. coli decreased apoptosis below spontaneous apoptosis, further indicating that both pro- and anti-apoptotic pathways are triggered by receptor-mediated phagocytosis.Type 1 fimbria-expressing E. coli adhering to neutrophils resisted ingestion, and induced a ROS-dependent apoptosis by a cooperative effect of the FimH adhesin and LPS. To explore how compartmentalization of ROS during neutrophil activation was involved in modulating apoptosis, we evaluated the stability of lysosomes. In contrast to phagocytosis of E. coli, the adhesive strain induced intracellular non-phagosomal ROS production which triggered early permeabilization and release of lysosomal enzymes to the cytosol. Cathepsin B and/or L were responsible for targeting of the pro-apoptotic Bcl-2 protein Bid, thereby inducing mitochondrial damage, and apoptosis. These data propose a novel pathway for ROS-induced apoptosis in human neutrophils, where the location of the ROS rather than production per se is important.Moreover, we found that pathogen-induced apoptotic neutrophils, in contrast to uninfected apoptotic neutrophils, activated blood-monocyte derived macrophages to increase their FcγRI surface expression and to produce large quantities of the pro-inflammatory cytokine TNF-α. This demonstrates that during the early phase of infection, pathogen-induced neutrophil apoptosis will help local macrophages to gain control over the microbes. Furthermore, we suggest that heat shock protein 60 and 70 represent a stress signal that enables macrophages to distinguish between, and react differently to, uninfected and inflammatory apoptotic neutrophils.
Subject headings and genre
- MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Mikrobiologi inom det medicinska området hsv//swe
- MEDICAL AND HEALTH SCIENCES Basic Medicine Microbiology in the medical area hsv//eng
- apoptosis
- cell death
- inflammation
- innate immunity
- microbiology
- neutrophil
- macrophage
- phagocyte
- Medical microbiology
- Medicinsk mikrobiologi
Added entries (persons, corporate bodies, meetings, titles ...)
- Stendahl, OlleLinköpings universitet,Medicinsk mikrobiologi,Hälsouniversitetet(Swepub:liu)ollst48 (thesis advisor)
- Zheng, LiminLinköpings universitet,Medicinsk mikrobiologi,Hälsouniversitetet(Swepub:liu)limzh30 (thesis advisor)
- Zhivotovsky, Boris,ProfessorInstitutet för Miljömedicin, Karolinska Institutet, Stockholms universitet, Stockholm (opponent)
- Linköpings universitetMedicinsk mikrobiologi (creator_code:org_t)
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