Microglia in the degenerating brain are capable of phagocytosis of beads and of apoptotic cells, but do not efficiently remove PrP^Sc, even upon LPS stimulation

Abstract

Despite the phagocytic machinery available to microglia the aberrant amyloid proteins produced during Alzheimer's and prion disease, amyloid-β and PrPSc, are inefficiently cleared. We have shown that microglia in the ME7 model of prion disease show morphological evidence of activation, synthesize low levels of pro-inflammatory cytokines and are primed to produce exaggerated responses to subsequent inflammatory challenges. Whether these microglia engage in significant phagocytic activity in the disease per se, or upon subsequent inflammatory challenge is not clear. In the present study we show transcriptional activation of a large number of scavenger receptors (SRs), matrix metalloproteinases (MMPs), oxidative enzymes, and cathepsins in ME7 animals. Hippocampally-injected inert latex beads (6 μm) are efficiently phagocytosed by microglia of ME7 prion-diseased animals, but not by microglia in normal animals. Stimulation of ME7 animals with systemic bacterial endotoxin (lipopolysaccharide, LPS) induced further increases in SR-A2, MMP3, and urokinase plasminogen activator receptor (uPAR) but decreased, or did not alter, transcription of most phagocytosis-related genes examined and did not enhance clearance of deposited PrPSc. Furthermore, intracerebral injection with LPS (0.5 μg) induced marked microglial production of IL-1β, robust cellular infiltration and marked apoptosis but also did not induce further clearance of PrPSc. These data indicate that microglia in the prion-diseased brain are capable of phagocytosis per se, but show limited efficacy in removing PrPSc even upon marked escalation of CNS inflammation. Furthermore, microglia/macrophages remain IL-1β-negative during phagocytosis of apoptotic cells. The data demonstrate that phagocytic activity and pro-inflammatory microglial phenotype do not necessarily correlate. © 2010 Wiley-Liss, Inc.

Mesenchymal Stem Cells Shape Microglia Effector Functions Through the Release of CX3CL1

“…These data demonstrate that MSC, through the release of CX3CL1, may enable microglia to dissociate phagocytic activity from the release of proinflammatory molecules [44] thus enhancing its homeostatic role in the maintenance of a healthy CNS, possibly through an efficient removal of apoptotic cells and phagocytosis of cellular debris and fostering a proregenerative environment within the CNS [30,43].…”

Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains

“…Together with our previous findings that depletion of microglia enhances prion replication in organotypic cerebellar slices (Falsig, et al, 2008), we hypothesize that the availability of microglia, and perhaps a basal level of activation, may be crucial for phagocytosis, whereas further activation does not appear to augment the clearance of prions. Accordingly, lipopolysaccharide-stimulated microglial activation did not enhance further phagocytosis of prions (Hughes, et al, 2010).…”

NTPDase1 activity attenuates microglial phagocytosis

“…Such treatments can irrevocably change the cellular phenotype, and extrapolation of the obtained data to the microglia in tissue surroundings should be treated with caution. In vivo studies, where fluorescent particles were injected in the tissue and phagocytosis was evaluated using morphological methods are difficult to quantify [24]. We have therefore studied phagocytosis in acute brain slices.…”