Dataset Information

Disinhibition of Cathepsin C Caused by Cystatin F Deficiency Aggravates the Demyelination in a Cuprizone Model.

ABSTRACT: Although the precise mechanism underlying initial lesion development in multiple sclerosis (MS) remains unclear, CNS inflammation has long been associated with demyelination, and axonal degeneration. The activation of microglia/macrophages, which serve as innate immune cells in the CNS, is the first reaction to even minor pathologic changes in the CNS and is considered an initial pathogenic event in MS. Microglial activation accompanies a variety of gene expressions, including cystatin F (Cys F), which belongs to the cystatin superfamily and is one of the cathepsin inhibitors. In our previous study we showed that Cys F has a unique expression pattern in microglia/macrophages in the demyelination process. Specifically, the timing of Cys F induction correlated with ongoing demyelination, and the sites of Cys F expression overlapped with areas of remyelination. Cys F induction ceased in chronic demyelination when remyelination capacity was lost, suggesting that Cys F expressed by microglia/macrophages may play an important role in demyelination and/or remyelination. The functional role of Cys F in demyelinating disease of the CNS, however, is unclear. Cys F gene knockout mice were used in the current study to clarify the functional role of Cys F in the demyelination process in a cuprizone-induced demyelination animal model. We demonstrated that absence of the Cys F gene and the resulting disinhibition of cathepsin C (Cat C) aggravates the demyelination, and this finding may be related to the increased expression of the glia-derived chemokine, CXCL2, which may attract inflammatory cells to sites of myelin sheath damage. This effect was reversed by knock down of the Cat C gene. The findings gain further insight to function of Cat C in pathophysiology of MS, which may have implications for therapeutics for the prevention of neuroinflammation-involved neurological disorders in the future.

SUBMITTER: Liang J

PROVIDER: S-EPMC5175397 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Disinhibition of Cathepsin C Caused by Cystatin F Deficiency Aggravates the Demyelination in a Cuprizone Model.

Liang Junjie J Li Ning N Zhang Yanli Y Hou Changyi C Yang Xiaohan X Shimizu Takahiro T Wang Xiaoyu X Ikenaka Kazuhiro K Fan Kai K Ma Jianmei J

Frontiers in molecular neuroscience 20161221

Although the precise mechanism underlying initial lesion development in multiple sclerosis (MS) remains unclear, CNS inflammation has long been associated with demyelination, and axonal degeneration. The activation of microglia/macrophages, which serve as innate immune cells in the CNS, is the first reaction to even minor pathologic changes in the CNS and is considered an initial pathogenic event in MS. Microglial activation accompanies a variety of gene expressions, including cystatin F (Cys F) ...[more]

PMID: 28066178

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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.

Project description:Multiple sclerosis (MS) is a chronic inflammatory CNS disease, which causes demyelinated lesions and damages white and gray matter regions. Aging is a significant factor in the progression of MS, and microglia, the immune cells of the CNS tissue, play an important role in all disease stages. During aging, microglia are functionally altered. These age-related changes probably already begin early and might influence the progression of CNS pathologies. The aim of the present study was to investigate whether microglia in the middle-aged CNS already react differently to demyelination. For this purpose, several microglia markers (ionized calcium binding adaptor molecule 1 (Iba-1), P2RY12, F4/80, CD68, major histocompatibility complex II (MHCII), macrophage receptor with collagenous structure (Marco), Translocator protein 18 kD (TSPO), CD206, and CD163) were analyzed in the acute cuprizone demyelination model in young (2-month-old) and middle-aged (10-month-old) mice. In addition, microglial proliferation was quantified using double-labeling with proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU), which was injected with the onset of remyelination. To compare age-related microglial changes during de- and remyelination in both gray and white matter, the hilus of the dorsal hippocampal dentate gyrus (DG) and the splenium of the corpus callosum (CC) were analyzed in parallel. Age-related changes in microglia of healthy controls were more pronounced in the analyzed gray matter region (higher levels of F4/80 and Marco as well as lower expression of CD68 in middle-aged mice). During de- and remyelination, a stronger increase of the microglial markers Iba-1, CD68 and TSPO was observed in the splenium of the younger groups. There was a significant reduction of P2RY12 during demyelination, however, this was age- and region-dependent. The induction of the anti-inflammatory markers CD206 and CD163 was stronger in the middle-aged group, but also differed between the two analyzed regions. De- and remyelination led to a significant increase in PCNA+ microglia only in young groups within the white matter region. The number of BrdU+ microglia was not changed during de- or remyelination. These results clearly show that microglia are already altered during middle-age and also react differently to CNS demyelination, however, this is highly region-dependent.

Dataset Information

Disinhibition of Cathepsin C Caused by Cystatin F Deficiency Aggravates the Demyelination in a Cuprizone Model.

Publications

Disinhibition of Cathepsin C Caused by Cystatin F Deficiency Aggravates the Demyelination in a Cuprizone Model.

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