Abstract
BackgroundThere is growing evidence that the death receptor CD95 has a wider role in non-apoptotic functions. In the brain, it may contribute to neural death and to the associated inflammatory reaction via a non-apoptotic pathway. Brain injury triggers an inflammatory reaction in which the CD95/CD95L system acts principally through peripheral cells recruited to the lesion. In cases of inflammation within the brain, with no blood–brain barrier leakage, the role of the CD95/CD95L system is thus unclear. We investigated the possible role of CD95 and CD95L in such conditions, by studying the relationships between glial cell activation, neuron death and CD95/CD95L expression in the cerebellum of the Lurcher (Grid2Lc/+) mutant mouse, a model of cerebellar neurodegeneration.MethodsGlial cells in slices of wild-type and Lurcher mouse cerebella were observed by light microscopy at various ages overlapping periods of neuron loss and of pre- and post-neurodegeneration. Subcellular organization was studied by electron microscopy. We assessed CD95 levels by western blotting, RT-PCR and glial cell cultures. The levels of CD95L and IL-6 were studied by ELISA and a biological assay, respectively.ResultsIn the Grid2Lc/+cerebellum, neuron loss triggers a typical, but abnormally persistent, inflammatory reaction. We identified two phases of astrogliosis: an early burst of large glial cell activation, peaking at postnatal days 25 to 26, coinciding with peak cerebellar neuron loss, followed by a long period of slow decline indicating that the strength of the glial reaction is modulated by neuron mortality rates. Comparisons of time-courses of glial cell activation, cytokine production and neuron loss revealed that the number of surviving neurons decreased as CD95 increased. Thus, CD95 cannot be directly involved in neuron death, and its role must be limited to a contribution to the inflammatory reaction. The upregulation of CD95 likely on astrocytes coincides with increases in the levels of IL-6, a cytokine produced principally by astrocytes, and soluble CD95L.ConclusionsThese results suggest that CD95 and soluble CD95L contribute, via non-apoptotic signaling, to the inflammatory reaction initiated early in neuron death within the Grid2Lc/+ cerebellum.
Highlights
There is growing evidence that the death receptor CD95 has a wider role in non-apoptotic functions
These authors demonstrated that peripheral cell CD95L expression, which is upregulated by the lesion, is required for the recruitment of peripheral myeloid cells to the injured tissue and contributes to neural cell loss by acting on peripheral myeloid cells, rather than via direct CD95-induced apoptosis in CD95-bearing resident neural cells [3]
We investigated the possible role of the CD95/CD95L system in the mechanism of neuronal death and in the inflammatory response, as an intrinsic component of the glial reaction in the Grid2Lc/+ cerebellum
Summary
There is growing evidence that the death receptor CD95 has a wider role in non-apoptotic functions. Inflammation resulting from trauma or ischemia reperfusion injury includes endothelial damage, the release of proinflammatory mediators, changes in vascular permeability, infiltration with peripheral inflammatory cells and the activation of microglia, the innate immune cells of the brain, and astrocytes It is marked by the recruitment of peripheral blood cells and the formation of a scar. CD95 (Fas, APO-1), which was initially identified as a death receptor, and its cognate ligand (CD95L, Fas-L) are both expressed in the brain They are thought to contribute to the inflammatory reaction through non-apoptotic signaling, mediating proinflammatory responses and triggering the recruitment of peripheral macrophages and leukocytes to the site of inflammation [1,2]. Natural mutant mice, such as the ataxic Lurcher (Grid2Lc/+) mouse, which displays cerebellar neurodegeneration, are valuable for investigations of the role of the CD95/CD95L system in this context making use of our extensive knowledge of cerebellar neurodegeneration in this mutant [8]
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