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Role of alveolar epithelial cells in macrophage responses against mycobacterial infections
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. (Immunology)
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis aimed to investigate the role of alveolar epithelial cells (AEC) on immune responses against mycobacterial infections, specifically, the role of AEC in modulating macrophage functions through the secretion of broad variety of factors.

In paper I, we compared murine AEC with interstitial macrophages (PuM) in their ability to take up and control mycobacterial growth and their capacity as antigen-presenting cells. We found that AEC were able to internalize and control bacterial growth and present antigens to T cells from immunized mice. In addition, both AEC and PuM exhibited distinct patterns of secreted factors, and a more comprehensive profile of AEC responses revealed that AEC were able to secrete different factors important to generate various effects in other cells. Paper II: Since AEC secrete a broad variety of factors, we hypothesized that being in the interface; AEC may play an important role in transmitting signals from the external to the internal compartment and in modulating the activity of PuM. Thus, we prepared AEC-derived media and tested their effect on bacteria and a number of macrophage functions a) migration, b) phagocytosis and control of intracellular bacterial growth, and c) alteration in cell morphology and expression of surface markers. We found that AEC-secreted factors had a dual effect, in one hand controlling bacterial growth and on the other hand increasing macrophage activity. In paper III, we first investigated the responsible mechanisms of intracellular bacterial growth control mediated by AEC-derived media. We found that infected macrophages upon AEC-secreted factors increased the control of intracellular bacterial growth by iNOS-independent pathways. Compared with other macrophage types, PuM, did not control the intracellular bacterial growth upon the well-known potent macrophage activator, IFN-γ. We found that SOCS1 was involved in the un-responsiveness to IFN-γ by PuM to control the intracellular bacterial growth. We suggested that PuM are restricted in their inflammatory responses perhaps for avoiding tissue damage.

Overall, the current findings highlight the importance of AEC in the defense against bacterial infection in the lungs by secreting factors involved in activation and differentiation of immune cells such as macrophages.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2013. , 59 p.
Keyword [en]
Lung, alveolar epithelial cells, macrophages, AEC-derived media, control of intracellular bacterial growth, mycobacterial infections
National Category
Immunology
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-86776ISBN: 978-91-7447-631-6 (print)OAI: oai:DiVA.org:su-86776DiVA: diva2:589388
Public defence
2013-02-22, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.

Available from: 2013-01-31 Created: 2013-01-18 Last updated: 2013-01-29Bibliographically approved
List of papers
1. The Role of Alveolar Epithelial Cells in Initiating and Shaping Pulmonary Immune Responses: Communication between Innate and Adaptive Immune Systems
Open this publication in new window or tab >>The Role of Alveolar Epithelial Cells in Initiating and Shaping Pulmonary Immune Responses: Communication between Innate and Adaptive Immune Systems
Show others...
2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2, e32125- p.Article in journal (Refereed) Published
Abstract [en]

Macrophages and dendritic cells have been recognized as key players in the defense against mycobacterial infection. However, more recently, other cells in the lungs such as alveolar epithelial cells (AEC) have been found to play important roles in the defense and pathogenesis of infection. In the present study we first compared AEC with pulmonary macrophages (PuM) isolated from mice in their ability to internalize and control Bacillus Calmette-Guerin (BCG) growth and their capacity as APCs. AEC were able to internalize and control bacterial growth as well as present antigen to primed T cells. Secondly, we compared both cell types in their capacity to secrete cytokines and chemokines upon stimulation with various molecules including mycobacterial products. Activated PuM and AEC displayed different patterns of secretion. Finally, we analyzed the profile of response of AEC to diverse stimuli. AEC responded to both microbial and internal stimuli exemplified by TLR ligands and IFNs, respectively. The response included synthesis by AEC of several factors, known to have various effects in other cells. Interestingly, TNF could stimulate the production of CCL2/MCP-1. Since MCP-1 plays a role in the recruitment of monocytes and macrophages to sites of infection and macrophages are the main producers of TNF, we speculate that both cell types can stimulate each other. Also, another cell-cell interaction was suggested when IFNs (produced mainly by lymphocytes) were able to induce expression of chemokines (IP-10 and RANTES) by AEC involved in the recruitment of circulating lymphocytes to areas of injury, inflammation, or viral infection. In the current paper we confirm previous data on the capacity of AEC regarding internalization of mycobacteria and their role as APC, and extend the knowledge of AEC as a multifunctional cell type by assessing the secretion of a broad array of factors in response to several different types of stimuli.

National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-80143 (URN)10.1371/journal.pone.0032125 (DOI)000303003500037 ()
Note

AuthorCount:6;

Available from: 2012-09-17 Created: 2012-09-12 Last updated: 2017-12-07Bibliographically approved
2. Alveolar epithelial cells are critical in protection of the respiratory tract by secretion of factors able to modulate the activity of pulmonary macrophages and directly control bacterial growth
Open this publication in new window or tab >>Alveolar epithelial cells are critical in protection of the respiratory tract by secretion of factors able to modulate the activity of pulmonary macrophages and directly control bacterial growth
2013 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 81, no 1, 381-389 p.Article in journal (Refereed) Published
Abstract [en]

The respiratory epithelium is a physical and functional barrier actively involved in the clearance of environmental agents. The alveolar compartment is lined with membranous pneumocytes known as type I alveolar epithelial cells (AEC I), and granular pneumocytes, type II alveolar epithelial cells (AEC II). AEC II are responsible for epithelial reparation upon injury and ion transport and are very active immunologically contributing to lung defense by secreting antimicrobial factors. AEC II also secrete a broad variety of factors such as cytokines and chemokines involved in activation and differentiation of immune cells and are able to present antigen to specific T cells. Another cell type important in lung defense is the pulmonary macrophage (PuM). Considering the architecture of the alveoli, a good communication between the external and the internal compartments is crucial to mount effective responses. Our hypothesis is that being in the interface; AEC may play an important role in transmitting signals from the external to the internal compartment and in modulating the activity of PuM. For this, we collected supernatants from AEC unstimulated or stimulated in vitro with lipopolysaccharide (LPS). These AEC-conditioned media were used in various setups to test for the effect on a number of macrophage functions: a) migration; b) phagocytosis and intracellular control of bacterial growth and c) phenotypic changes and morphology. Finally, we tested the direct effect of AEC-conditioned media on bacterial growth. We found that AEC-secreted factors had a dual effect, in one hand controlling bacterial growth and on the other hand increasing macrophage activity.

National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-86790 (URN)10.1128/IAI.00950-12 (DOI)000316298000039 ()
Available from: 2013-01-18 Created: 2013-01-18 Last updated: 2017-12-06Bibliographically approved
3. Soluble factors from alveolar epithelial cells increase intracellular killing of BCG by macrophages through nitric oxide independent mechanisms
Open this publication in new window or tab >>Soluble factors from alveolar epithelial cells increase intracellular killing of BCG by macrophages through nitric oxide independent mechanisms
(English)Manuscript (preprint) (Other academic)
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-86792 (URN)
Available from: 2013-01-18 Created: 2013-01-18 Last updated: 2013-01-21Bibliographically approved

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