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CNS-specific expression of C3a and C5a exacerbate demyelination severity in the cuprizone model.

ABSTRACT: 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.

SUBMITTER: Ingersoll SA

PROVIDER: S-EPMC2993815 | biostudies-literature | 2010 Nov-Dec

REPOSITORIES: biostudies-literature

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CNS-specific expression of C3a and C5a exacerbate demyelination severity in the cuprizone model.

Ingersoll Sarah A SA Martin Carol B CB Barnum Scott R SR Martin Brian K BK

Molecular immunology 20100901 1-3

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 sligh ...[more]

PMID: 20813409

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Project description:BACKGROUND:Various studies by MRI exhibit that the corpus callosum (CC) is the most vulnerable to cuprizone administration, detecting the demyelination and remyelination process using different MRI parameters are, however, lacking. PURPOSE:To investigate the sensitivity of multiparametric MRI both in vivo and ex vivo for demyelination and remyelination. STUDY TYPE:Prospective. ANIMAL MODEL:A cuprizone mice model with an age-matched control group (n = 5), 4-week cuprizone exposure group followed by 9-week on a normal diet (n = 6), and a 13-week cuprizone exposure group (n = 6). FIELD STRENGTH/SEQUENCE:3D gradient recalled echo, T2 -weighted, and diffusion tensor imaging (DTI) at 7.0T and 9.4T. ASSESSMENT:Quantification of DTI metrics, quantitative susceptibility mapping (QSM), and T2 -weighted imaging intensity in major white matter bundles. STATISTICAL TESTS:Nonparametric permutation tests were used with a cluster-forming threshold as 3.09 (equivalent to P = 0.001), and the significant level as P = 0.05 with family-wise correction. RESULTS:In vivo susceptibility values increased from -11.7 to -0.7 ppb (P < 0.001) in CC and from -13.7 to -5.1 ppb (P < 0.001) in the anterior commissure (AC) after the 13-week cuprizone exposure. Ex vivo susceptibility values increased from -25.4 to 7.4 ppb (P < 0.001) in CC and from -41.6 to -15.8 ppb (P < 0.001) in AC. Susceptibility values showed high variations to demyelination for in vivo studies (94.0% in CC, 62.8% in AC). Susceptibility values exhibited higher variations than radial diffusivity for ex vivo studies (129.1% vs. 28.3% in CC, 62.0% vs. 25.0% in AC). In addition to the differential susceptibility variations in different white matter tracts, intraregional demyelination variation was also present not only in CC but also in the AC area by voxel-based analysis. DATA CONCLUSION:QSM is sensitive to the demyelination process of cuprizone exposure, which can be a complementary technique to conventional T2 -weighted images and DTI metrics. LEVEL OF EVIDENCE:2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:1852-1865.

Dataset Information

CNS-specific expression of C3a and C5a exacerbate demyelination severity in the cuprizone model.

Publications

CNS-specific expression of C3a and C5a exacerbate demyelination severity in the cuprizone model.

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