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Slow degradation in phagocytic astrocytes can be enhanced by lysosomal acidification
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
University of Pennsylvania. (Department of Anatomy and Cell Biology)
Uppsala University, Science for Life Laboratory, SciLifeLab. (Centre for Image Analysis (CBA))
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
2015 (English)In: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 63, no 11, 1997-2009 p.Article in journal (Refereed) Published
Abstract [en]

Inefficient lysosomal degradation is central in the development of various brain disorders, but the underlying mechanisms and the involvement of different cell types remains elusive. We have previously shown that astrocytes effectively engulf dead cells, but then store, rather than degrade the ingested material. In the present study we identify reasons for the slow digestion and ways to accelerate degradation in primary astrocytes. Our results show that actin-rings surround the phagosomes for long periods of time, which physically inhibit the phago-lysosome fusion. Furthermore, astrocytes express high levels of Rab27a, a protein known to reduce the acidity of lysosomes by Nox2 recruitment, in order to preserve antigens for presentation. We found that Nox2 colocalizes with the ingested material, indicating that it may influence antigen processing also in astrocytes, as they express MHC class II. By inducing long-time acidification of astrocytic lysosomes using acidic nanoparticles, we could increase the digestion of astrocyte-ingested, dead cells. The degradation was, however, normalized over time, indicating that inhibitory pathways are up-regulated in response to the enhanced acidification.

Place, publisher, year, edition, pages
2015. Vol. 63, no 11, 1997-2009 p.
Keyword [en]
Phagocytosis, in vitro model, digestion, antigen presentation, Rab27a, Nox2, pHrodo, actin, Latrunculin
National Category
Research subject
URN: urn:nbn:se:uu:diva-215150DOI: 10.1002/glia.22873ISI: 000361185000008OAI: oai:DiVA.org:uu-215150DiVA: diva2:686337
Magnus Bergvall Foundation

Manuscript title: Degradation of Ingested Dead Cells in Phagocytic Astrocytes is Tightly Regulated, but can be Enhanced by Lysosomal Acidifcatio

Available from: 2014-01-11 Created: 2014-01-11 Last updated: 2015-10-08Bibliographically approved
In thesis
1. Cellular and Molecular Responses to Traumatic Brain Injury
Open this publication in new window or tab >>Cellular and Molecular Responses to Traumatic Brain Injury
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Traumatic brain injury (TBI) is a relatively unknown disease considering the tens of millions of people affected around the world each year. Many TBI patients die from their injuries and survivors often suffer from life-long disabilities. The primary injury initiates a variety of cellular and molecular processes that are both beneficial and detrimental for the brain, but that are not fully understood. The focus of this thesis has been to study the role of astrocytes in clearance of dead cells after TBI and to identify injury specific proteins that may function as biomarkers, by using cell cultures, animal models and in cerebrospinal fluid (CSF) from TBI patients.

The result demonstrates a new function in that astrocytes, the most numerous cell type in the brain, engulf dead cells after injury both in cell cultures and in adult mice and thereby save neurons from contact-induced apoptosis. Astrocytes are effective phagocytes, but degrade the ingested dead cells very slowly. Moreover, astrocytes express the lysosome-alkalizing proteins Rab27a and Nox2 as well as major histocompatibility complex class II, the receptors on which antigens are being presented. By lowering the pH of the lysosomes with acidic nanoparticles, the degradation increases, but the astrocytes still remained less effective than macrophages. Taken together, the data indicates that the low acidification in astrocytes can preserve antigens and that astrocytes may be able to activate T cells.

The expression and secretion of injury-specific proteins was studied in a cell culture model of TBI by separate mass spectrometry analysis of cells and medium. Interestingly, close to 30 % of the injury-specific proteins in medium are linked to actin, for example ezrin of the ezrin/radixin/moesin (ERM) protein family. Ezrin, but none of the other ERM proteins or actin, is actively secreted after injury. Extracellular ezrin also increases in CSF in response to experimental TBI in rats and is present in CSF from TBI patients, indicating that ezrin is a potential biomarker for TBI. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 59 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 966
Traumatic Brain Injury, Astrocyte, Apoptosis, Biomarkers, Ezrin, Actin, Extracellular Proteins, Degradation, Lysosome, Antigen Presentation
National Category
Research subject
Neuroscience; Neurosurgery
urn:nbn:se:uu:diva-215154 (URN)978-91-554-8845-1 (ISBN)
Public defence
2014-02-28, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Available from: 2014-02-06 Created: 2014-01-11 Last updated: 2014-02-10

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Lööv, CamillaErlandsson, Anna
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