Engulfing Astrocytes Protect Neurons from Contact-Induced Apoptosis following Injury

Abstract

Clearing of dead cells is a fundamental process to limit tissue damage following brain injury. Engulfment has classically been believed to be performed by professional phagocytes, but recent data show that non-professional phagocytes are highly involved in the removal of cell corpses in various situations. The role of astrocytes in cell clearance following trauma has however not been studied in detail. We have found that astrocytes actively collect and engulf whole dead cells in an in vitro model of brain injury and thereby protect healthy neurons from bystander cell death. Time-lapse experiments showed that migrating neurons that come in contact with free-floating cell corpses induced apoptosis, while neurons that migrate through groups of dead cells, garnered by astrocytes, remain unaffected. Furthermore, apoptotic cells are present within astrocytes in the mouse brain following traumatic brain injury (TBI), indicating a possible role for astrocytes in engulfment of apoptotic cells in vivo. qRT-PCR analysis showed that members of both ced pathways and Megf8 are expressed in the cell culture, indicating their possible involvement in astrocytic engulfment. Moreover, addition of dead cells had a positive effect on the protein expression of MEGF10, an ortholog to CED1, known to initiate phagocytosis by binding to phosphatidylserine. Although cultured astrocytes have an immense capacity for engulfment, seemingly without adverse effects, the ingested material is stored rather than degraded. This finding might explain the multinuclear astrocytes that are found at the lesion site in patients with various brain disorders.

Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

“…It is possible that astrocytes have a low rate of digestion as compared to other typical phagocytes such as microglial cells. In this sense, poor degradation of engulfed dead cells in astrocytes has been reported previously (Lööv et al, 2012). These authors indicate that the slow digestion of the engulfed material in astrocytes is due, at least in part, to the actin‐rings that surround the phagosomes for long periods of time, which physically inhibit the phagolysosome fusion (Lööv, Mitchell, Simonsson, & Erlandsson, 2015).…”

Ganglioside accumulation in activated glia in the developing brain: comparison between WT and GalNAcT KO mice

“…This is compatible with degradation of phagocytosed material from degenerating neurons rich in gangliosides, and correlates with the rapid appearance of astrocytic GM2 in the deep cortical layers/corpus callosum area (Area II) where degenerating neurites are present ( 14 ) for potential engulfment. Phagocytosis by astrocytes has been documented in, for example, synaptic elimination during development ( 58 ) and elimination of dead cells following acute traumatic brain injury ( 59 ). The second explanation, astrocyte-intrinsic changes in gangliosides, is supported by the observed increase in GM2 + GFAP + cells found with LPS treatment ( Fig.…”

Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer’s Disease

“…Reactive astrocytes are phagocytic cells that are able to ingest dead cells, neuronal synapses, and protein aggregates of Aβ and α-synuclein [18][19][20][21][22]. Especially in early stages of AD, astrocytes appear to be even more efficient than microglia in engulfing Aβ [22].…”