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Apoptotic neutrophils augment the inflammatory response to Mycobacterium tuberculosis infection in human macrophages
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, e101514- p.Article in journal (Refereed) Published
Abstract [en]

Macrophages in the lung are the primary cells being infected by Mycobacterium tuberculosis (Mtb) during tuberculosis. Innate immune cells such as macrophages and neutrophils are first recruited to the site of infection, and mount the early immune protection against this intracellular pathogen. Neutrophils are short-lived cells and removal of apoptotic cells by resident macrophages is a key event in the resolution of inflammation and tissue repair. Such anti-inflammatory activity is not compatible with effective immunity to intracellular pathogens. We therefore investigated how uptake of apoptotic neutrophils by Mtb-activated human monocyte-derived macrophages modulates their function. We show that Mtb infection exerts a potent pro-inflammatory activation of human macrophages with enhanced gene activation and release of several cytokines (TNF, IL-1ß, IL-6, IL-18 and IL-10). This response was augmented by apoptotic neutrophils. Macrophages containing both Mtb and apoptotic cells showed a stronger cytokine expression than non-infected cells. The enhanced macrophage response is linked to apoptotic neutrophil-driven activation of the NLRP3 inflammasome and subsequent IL-1β signalling. We also demonstrate that apoptotic neutrophils not only modulate the inflammatory response, but also enhance the capacity of infected macrophages to control intracellular growth of virulent Mtb. Taken together, these results suggest a novel role for apoptotic neutrophils in the modulation of the macrophage-dependent inflammatory response, which can contribute to the early control of Mtb infection.

Place, publisher, year, edition, pages
PLoS , 2014. Vol. 9, no 7, e101514- p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-100888DOI: 10.1371/journal.pone.0101514ISI: 000338637300054OAI: oai:DiVA.org:liu-100888DiVA: diva2:664164
Available from: 2013-11-14 Created: 2013-11-14 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Mycobacterium tuberculosis and the human macrophage: shifting the balance through inflammasome activation
Open this publication in new window or tab >>Mycobacterium tuberculosis and the human macrophage: shifting the balance through inflammasome activation
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mycobacterium tuberculosis is a very successful pathogen and tuberculosis constitutes a major threat to global health worldwide. The World Health Organization (WHO) estimates that almost nine million new cases and 1.5 million deaths occur annually and the situation is worsened by increased antibiotic resistance and an extreme synergism with the HIV pandemic. M. tuberculosis primarily affects the lungs where the infection can lead to either eradication of the bacteria or the initiation of an immune response that culminates in the formation of a large cluster of immune cells termed granulomas. In these granulomas, the bacteria can either replicate and cause disease with the ultimate goal of spreading to new hosts or cause latent tuberculosis, which can persist for decades. The tools available to manage the disease are currently suboptimal and include lengthy antibiotic treatments and an inefficient vaccine resulting in poor protection. On a cellular level, M. tuberculosis primarily infects the cell designed to recognize, ingest and eradicate bacteria, namely the human macrophage. Following recognition, the macrophage phagocytoses the bacterium and tries to kill it using an array of different effector mechanisms including acidification of the bacterium-containing vacuole, different degradative enzymes and the generation of radicals. However, the bacterium is able to circumvent many of these harmful effects, leading to a tug-of-war between the bacterium  and host macrophage. This thesis aims at studying the interaction between the human macrophage and M. tuberculosis to identify host factors critical for controlling growth of the bacteria. More specifically, it focuses on the role of an intracellular receptor protein called NLRP3 and its downstream effects. NLRP3 is activated in human macrophages infected by M. tuberculosis and upon activation it forms a multi-protein complex known as the inflammasome. This protein complex is known to induce the production of the proinflammatory cytokine IL-1β and specialized forms of macrophage cell death. We hypothesized that stimulating this pathway would have a beneficial effect for the host macrophage during infection with M. tuberculosis.

To allow us to follow interaction between M. tuberculosis and the human macrophage, we first developed a luminometry-based method of measuring bacterial numbers and following bacterial growth over several days in infected cells. With this new assay we showed that low numbers of bacteria induced very low levels of IL-1β and failed to induce any type of cell death in the macrophage. However, when a critical number of bacteria were reached, the infected macrophages underwent necrosis, which was accompanied by high levels of IL-1β. We were also able to show that addition of vitamin D, which has been implicated as an important factor for increased killing capacity of infected macrophages, increased the production of IL-1β, which coincided with increased killing of M. tuberculosis. This effect was seen specifically in cells from patients with active tuberculosis, suggesting that these cells are primed to respond to vitamin D and increased levels of IL-1β. Furthermore, we also showed that increasing production of IL-1β by stimulating infected macrophages with apoptotic neutrophils in turn drives the production of other proinflammatory cytokines. Lastly, we showed that gain-of-function polymorphisms in inflammasome components linked to increased inflammasome activation and IL-1β production promotes bacterial killing in human macrophages. In conclusion, the work presented in this thesis shows  that by enhancing the functions of the inflammasome, it is possible to tip the balance between the human macrophage and M. tuberculosis in favor of the host cell.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 97 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1372
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-100890 (URN)10.3384/diss.diva-100890 (DOI)978-91-7519-558-2 (ISBN)
Public defence
2013-12-11, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
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Available from: 2013-11-14 Created: 2013-11-14 Last updated: 2013-11-14Bibliographically approved

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Andersson, HenrikEklund, DanielNgoh, EylerPersson, AlexanderAndersson, BlankaSvensson, KristofferLerm, MariaBlomgran, RobertStendahl, Olle

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