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Apoptotic neutrophils activates the inflammatory response in macrophages –increased capacity to handle intracellular infection
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
Abstract [en]

Inflammation is essential to eradicate invading pathogens but an uncontrolled inflammation may develop into chronic inflammation and extensive tissue destruction unable of effectively controlling infections. At the site of infection, macrophages are the major regulators of the inflammatory response through balanced release of pro- or anti-inflammatory cytokines and therefore a key cell in the resolution of inflammation. Neutrophils effectively phagocytose and kill pathogens but they are short-lived and removal of these dead cells by macrophages is a key event in the resolution of inflammation and tissue repair.

However, down-regulation of the immune response by apoptotic cells would in the presence of pathogens be detrimental to the host. In contrast to resolution of inflammation, we show that in the presence of microbial stimuli, apoptotic neutrophils in fact exert a potent pro-inflammatory activation of macrophages. This augmentation of the pro-inflammatory response is dependent on uptake of the apoptotic cells by the macrophage. In addition to secretion of TNF-α, presence of apoptotic neutrophils enhanced the capacity of the stimulated macrophages to kill intracellular Mycobacterium tuberculosis. This presents a novel role for apoptotic neutrophils in the modulation of the macrophage-dependent inflammatory response, and control of intracellular infections.

National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-20837OAI: oai:DiVA.org:liu-20837DiVA: diva2:236462
Available from: 2009-10-06 Created: 2009-09-23 Last updated: 2009-11-17Bibliographically approved
In thesis
1. Apoptotic neutrophils enhance the immune response against Mycobacterium tuberculosis
Open this publication in new window or tab >>Apoptotic neutrophils enhance the immune response against Mycobacterium tuberculosis
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, a disease that for years was considered to belong of the past, but tuberculosis is back causing over 2 million deaths per year. The infection can be dormant for decades and an active immune response can prevent the infection from progressing into active disease. However, the HIV/AIDS epidemic has caused an alarming rise in tuberculosis cases.

The main infectious route for Mtb is through the airways into the lungs, where they encounter alveolar macrophages. Mtb are phagocytosed by these macrophages, but instead of being killing within the phagosome, Mtb modulates the cell to become a host in which the bacteria thrive. The lack of capacity to eradicate the infection stimulate cells of the immune system to gather around infected macrophages and form a granuloma that walls off the infection. Within this granuloma, Mtb can wait silently and later progress into active disease. However, only a fraction of exposed individuals develop disease, indicating that initial eradication of Mtb infections is possible. Such immediate response must be directed by the innate immunity comprised of phagocytes such as neutrophils (PMNs) and non-activated macrophages. Upon Mtb infection, macrophages become anergic and PMNs enter apoptosis. PMNs have a short lifespan and are cleared by neighbouring phagocytes, a mechanism described to resolve the inflammation and modulate tissue regeneration.

We found that Mtb-induced apoptosis in PMNs was not dependent on phagocytosis of the bacteria, indicating that Mtb have the capacity to induce apoptosis in multiple PMNs. Complement-mediated phagocytosis induce survival signals such as Akt in PMNs, but despite this, complement-opsonized Mtb was able to override the anti-apoptotic activation in the cells. Since phagocytes clear apoptotic cells, we investigated how clearance of Mtb-induced apoptotic PMNs affected macrophages. We found that Mtb-induced apoptotic PMNs inflicted pro-inflammatory activation of the macrophages that cleared them. In addition, this activation was mediated by Hsp72 released from the Mtb-induced apoptotic PMNs. Furthermore, apoptotic PMNs can work in synergy with phagocytosed Mtb to activate macrophages and enhance intracellular killing of Mtb.

Since dendritic cells are important for the regulation of immunity, we investigated whether Mtb-induced apoptotic PMNs affected the inflammatory response and maturation of dendritic cells. We found that Mtb-induced apoptotic PMNs trigger dendritic cells to enter a mature state able to activate naïve T-cell proliferation.

We propose that infected apoptotic PMNs is a potent activator of the inflammatory response during infections. Taken together, PMNs not only kill their share of pathogens but also modulate other immune cells, thereby forming a link between the early innate and the adaptive immune response during microbial challenge with Mtb.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 73 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1134
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-51467 (URN)978-91-7393-615-6 (ISBN)
Public defence
2009-08-24, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2009-11-17 Created: 2009-11-04 Last updated: 2009-11-19Bibliographically approved

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