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Mycobacterium tuberculosis Promotes Apoptosis in Human Neutrophils by Activating Caspase-3 and Altering Expression of Bax/Bcl-xL Via an Oxygen-Dependent Pathway
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
2002 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 168, no 12, 6358-6365 p.Article in journal (Refereed) Published
Abstract [en]

In addition to direct bactericidal activities, such as phagocytosis and generation of reactive oxygen species (ROS), neutrophils can regulate the inflammatory response by undergoing apoptosis. We found that infection of human neutrophils with Mycobacterium tuberculosis (Mtb) induced rapid cell death displaying the characteristic features of apoptosis such as morphologic changes, phosphatidylserine exposure, and DNA fragmentation. Both a virulent (H37Rv) and an attenuated (H37Ra) strain of Mtb were equally effective in inducing apoptosis. Pretreatment of neutrophils with antioxidants or an inhibitor of NADPH oxidase markedly blocked Mtb-induced apoptosis but did not affect spontaneous apoptosis. Activation of caspase-3 was evident in neutrophils undergoing spontaneous apoptosis, but it was markedly augmented and accelerated during Mtb-induced apoptosis. The Mtb-induced apoptosis was associated with a speedy and transient increase in expression of Bax protein, a proapoptotic member of the Bcl-2 family, and a more prominent reduction in expression of the antiapoptotic protein Bcl-xL. Pretreatment with an inhibitor of NADPH oxidase distinctly suppressed the Mtb-stimulated activation of caspase-3 and alteration of Bax/Bcl-xL expression in neutrophils. These results indicate that infection with Mtb causes ROS-dependent alteration of Bax/Bcl-xL expression and activation of caspase-3, and thereby induces apoptosis in human neutrophils. Moreover, we found that phagocytosis of Mtb-induced apoptotic neutrophils markedly increased the production of proinflammatory cytokine TNF-α by human macrophages. Therefore, the ROS-dependent apoptosis in Mtb-stimulated neutrophils may represent an important host defense mechanism aimed at selective removal of infected cells at the inflamed site, which in turn aids the functional activities of local macrophages.

Place, publisher, year, edition, pages
2002. Vol. 168, no 12, 6358-6365 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-26523Local ID: 11082OAI: oai:DiVA.org:liu-26523DiVA: diva2:247072
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-07Bibliographically approved
In thesis
1. Interaction Between Mycobacterium tuberculosis and Human Neutrophils
Open this publication in new window or tab >>Interaction Between Mycobacterium tuberculosis and Human Neutrophils
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mycobacterium tuberculosis, the etiologic agent of tuberculosis, is responsible for more deaths each year than any other single pathogen. Mononuclear phagocytes and T cells are crucially involved in the control and local containment of this infection. Less is known about the contribution of neutrophils to control tuberculosis. As one of the most efficient phagocytic cells of the immune system, neutrophils restrict the initial, local replication of numerous pathogens and thereby delay their systemic spread. Neutrophils immigrate quickly to the site of mycobacterial entry and are found in granulomas after infection with M. tuberculosis. The aims of this study were to investigate how neutrophils control M. tuberculosis in the acute phase of mycobacterial infection and the signaling pathways regulating these processes.

When neutrophils are exposed to mycobacteria, they exhibit the typical early bactericidal responses: phagocytosis, generation of reactive oxygen intermediate (ROI), degranulation and the killing of mycobacteria. While production of ROI and M. tuberculosis killing in neutrophils are calcium dependent events, phagocytosis of M. tuberculosis is a calcium-independent process. Measuring intracellular calcium concentration [(Ca+2)]i, revealed that there is no increase in the level of [(Ca+2)]i in single neutrophils upon ingestion of M. tuberculosis. Investigation of the M. tuberculosis-induced phagocytic pathway showed that stimulation of neutrophils by M. tuberculosis triggers tyrosine phosphorylation of PLCγ2 and its association with sch, an adapter protein, and that such association are critical for the M. tuberculosis-stimulated ROI production through activating p38 MAPK. During phagolysosome biogenesis, phagosomes containing M. tuberculosis fused sequentially with secondary granule and late endosomal vacuoles, while delivery of azurophil granule was inhibited. A complex of Rab5a-GTP and syntaxin-4 controlled this fusion process. We suggested that the retention of this complex on the mycobacterial phagosome might allow mycobacteria to avoid the usual physiological destination of phagocytic maturation. Neutrophils infected by M. tuberculosis underwent rapid apoptosis that was mediated by activation of caspase-3 and the expression of Bax and Bcl-x1, two antagonizing members of Bcl-2 family. The level of ROI production controlled this M. tuberculosis induced apoptotic pathway. Apoptotic neutrophils are removed by macrophages, which leads to an augmented mycobactericidal effect in these cells. The results from this work show that neutrophils play an efficient and important role in the early innate immune response against mycobacterial infection, a process that may influence the subsequent specific immune response at the site of infection.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2001. 71 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 679
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-28623 (URN)13779 (Local ID)91-7219-964-4 (ISBN)13779 (Archive number)13779 (OAI)
Public defence
2001-05-31, Berzeliussalen, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-09-07Bibliographically approved

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Perskvist, NasrinStendahl, OlleZheng, Limin

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