Expression of the anaphylatoxin C5a receptor in the oligodendrocyte lineage

doi:10.1016/S0006-8993(01)02003-0

Brain Research

Volume 894, Issue 2, 16 March 2001, Pages 321-326

https://doi.org/10.1016/S0006-8993(01)02003-0 Get rights and content

Abstract

Expression of the C5a receptor in the central nervous system has been demonstrated on microglia, astrocytes and neurons. In the present study, we demonstrate C5aR expression in vitro by rat and murine O2-A progenitor cells and oligodendrocytes. We also observed that in vitro differentiation of O2-A progenitors into mature oligodendrocytes is accompanied by down-regulation of C5aR mRNA expression. These results suggest that the C5aR may be a marker for oligodendroglial differentiation and play a role in oligodendrocyte function.

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Acknowledgements

This study was supported by NIH grant NS29719 (to S.R.B.), advanced post-doctoral fellowship (FA 1306) from the National Multiple Sclerosis Society (to S.N.) and RG-3837 awarded by the NMSS to SWL.

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The pathology associated with spinal cord injury (SCI) is caused not only by primary mechanical trauma, but also by secondary responses of the injured CNS. The inflammatory response to SCI is robust and plays an important but complex role in the progression of many secondary injury-associated pathways. Although recent studies have begun to dissect the beneficial and detrimental roles for inflammatory cells and proteins after SCI, many of these neuroimmune interactions are debated, not well understood, or completely unexplored. In this regard, the complement cascade is a key component of the inflammatory response to SCI, but is largely underappreciated, and our understanding of its diverse interactions and effects in this pathological environment is limited. In this review, we discuss complement in the context of SCI, first in relation to traditional functions for complement cascade activation, and then in relation to novel roles for complement proteins in a variety of models.
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Anaphylatoxins also bind C5a receptor-like 2 (C5L2), whose functions have not been clearly defined, but may act as a decoy or scavenger receptor (Klos et al., 2009). Previous studies have shown that astrocytes, microglia, neurons and oligodendrocytes express anaphylatoxin receptors (Davoust et al., 1999; Gasque et al., 1997; Gavrilyuk et al., 2005; Nataf et al., 2001). C3a and C5a signaling in the CNS can induce a wide range of functions depending upon the cell type and local environmental stimuli.
Demyelination in the central nervous system (CNS) is known to involve several immune effector mechanisms, including complement proteins. Local production of complement by glial cells in the brain can be both harmful and protective. To investigate the roles of C3a and C5a in demyelination and remyelination pathology we utilized the cuprizone model. Transgenic mice expressing C3a or C5a under the control of the glial fibrillary acidic protein (GFAP) promoter had exacerbated demyelination and slightly delayed remyelination in the corpus callosum compared to WT mice. C3a and C5a transgenic mice had increased cellularity in the corpus callosum due to increase activation and/or migration of microglia. Oligodendrocytes migrated to the corpus callosum in higher numbers during early remyelination events in C3a and C5a transgenic mice, thus enabling these mice to remyelinate as effectively as WT mice by the end of the 10 week study. To determine the effects of C3a and/or C5a on individual glial subsets, we created murine recombinant C3a and C5a proteins. When microglia and mixed glial cultures were stimulated with C3a and/or C5a, we observed an increase in the production of proinflammatory cytokines and chemokines. In contrast, astrocytes had decreased cytokine and chemokine production in the presence of C3a and/or C5a. We also found that the MAPK pathway proteins JNK and ERK1/2 were activated in glia upon stimulation with C3a and C5a. Overall, our findings show that although C3a and C5a production in the brain play a negative role during demyelination, these proteins may aid in remyelination.
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The cleavage product of C5, C5a, is an important anaphylatoxin. This inflammatory mediator exerts its effects by binding to the C5a receptor (C5aR, CD88), a member of the seven transmembrane-spanning G protein-coupled receptor family. Recent evidence has suggested that C5aR is expressed in diverse cell types including myeloid cells, endothelium and parenchymal cells in many tissues. Some data have suggested a role for C5a in neuroinflammation, however the molecular mechanisms responsible for C5aR expression in glial cells are largely unknown. In this report, we demonstrate higher levels of C5aR transcription in microglia compared to astrocytes. NF-YA protein from microglial nuclear extracts forms strong complexes with the C5aR CCAAT motif, suggesting regulation similar to that previously described in macrophages. In astrocytes, there is weak protein binding at the CCAAT box and reporter gene assays suggest minimal dependence upon this site for transcriptional regulation in primary astrocytes. Instead, there are several sites that exhibit some level of transcriptional control and the minimal construct directs significant promoter activity. These data suggest that C5aR transcriptional control in astrocytes is distinct from regulation in myeloid cells.

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Short communicationExpression of the anaphylatoxin C5a receptor in the oligodendrocyte lineage

Abstract

Section snippets

Acknowledgements

Neuroscience

J. Neuroimmunol.

Neurosci. Lett.

J. Neuroimmunol.

Trends Neurosci.

Neuroscience

Brain Res. Mol. Brain Res.

J. Neurosci. Methods

Pre-oligodendrocytes from adult human CNS

J. Neurosci.

Type 1 astrocytes and oligodendrocyte-type 2 astrocyte glial progenitors migrate toward distinct molecules

J. Neurosci. Res.

Characterization of complement anaphylatoxina and their biological responses

A neuronal C5a receptor and an associated apoptotic signal transduction pathway

J. Physiol. (Lond.)

Short communication
Expression of the anaphylatoxin C5a receptor in the oligodendrocyte lineage