title: Slow degradation in phagocytic astrocytes can be enhanced by lysosomal acidification.
abstract: 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. GLIA 2015;63:1997-2009.
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala University Hospital Ent 85, 2nd Fl., Uppsala, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Lööv
authors.affiliation: Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Claire H
authors.initials: CH
authors.lastname: Mitchell
authors.affiliation: SciLifeLab and Department of Computer Science, Electrical & Space Engineering, Luleå, University of Technology, Luleå, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Simonsson
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala University Hospital Ent 85, 2nd Fl., Uppsala, Sweden.|Department of Public Health and Caring Sciences, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Erlandsson
keywords: Nox2; Rab27a; digestion; glia; lysosome; nanoparticle; pHrodo; phagocytosis