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TSPO mediates neuroinflammation via Parkin and p62 regulation in microglia

Title
TSPO mediates neuroinflammation via Parkin and p62 regulation in microglia
Translated Title
미세아교세포에서의 Parkin 및 p62를 통한 TSPO의 신경 염증 반응 조절
Authors
Shim, Hyun Jung
DGIST Authors
Shim, Hyun Jung; Yu, Seong Woon; Choi, Ji Woong
Advisor(s)
Yu, Seong Woon
Co-Advisor(s)
Choi, Ji Woong
Issue Date
2016
Available Date
2016-02-12
Degree Date
2016. 2
Type
Thesis
Keywords
NeuroinflammationMicrogliaTSPOParkinp62신경염증반응미세아교세포
Abstract
Neuroinflammation has relevance to many neurodegenerative diseases. Although certain aspects of inflammatory responses have beneficial effects, uncontrolled inflammation may impair the maintenance of homeostasis and exacerbate disease states. Microglia, the major resident brain immune cells, are mainly associated with neuroinflammatory responses in the central nervous system. Under normal condition, deactivated microglia produce anti-inflammatory and neurotrophic factors. However, under exposure of invaded pathogen or tissue damage, microglia are activated and promote a pro-inflammatory response. The translocator protein 18 kDa (TSPO) is a five transmembrane protein localized in the outer mitochondrial membrane. The expression level of TSPO is increased by neuroinflammation in activated microglia and astrocytes. Although there is a close correlation between a high expression level of TSPO and neuroinflammation, it is not known how TSPO is involved in the regulation of neuroinflammation and microglia activation. To reveal the role of TSPO in the regulation of inflammation and the related mechanisms through which TSPO regulates neuroinflammation, we examined the effects of two TSPO ligands, PK11195 and Ro5-4864, and TSPO overexpression on the signaling molecules important in mediation of microglia activation. Lipopolysaccharide (LPS) treatment induced a robust increase in the production of inflammatory factors, such as nitric oxide (NO), tumor necrosis factors (TNF) -α and interlukin (IL) -6. TSPO overexpression significantly attenuated the production of pro-inflammatory cytokines. TSPO ligands inhibited mitogen-activated protein kinases (MAPK) pathway, especially Jun N-terminal kinase (JNK) and p38, but not Erk. In addition, TSPO overexpression or pretreatment with TSPO ligands reduced LPS-induced NF-κB transcriptional activity. These results demonstrate that TSPO negatively regulates neruroinflammation and microglia activation through the suppression of NF-κB and MAPK signaling pathways. Recently, the role and mechanisms of parkin in the regulation of inflammation has been reported. Because Parkin was recruited to mitochondria following LPS treatment, we confirmed the relationship between TSPO and Parkin in inflammation in microglia. Although Parkin has anti-inflammatory effects, TSPO knockdown blocked the inhibitory effects of Parkin against the production of pro-inflammatory cytokines. Futhermore, TSPO and Parkin suppressed inflammation via autophagy. However, TSPO knock-down increased p62 aggregation that reduced by Parkin. This study was aimed to investigate whether TSPO negatively regulates neuroinflammation and microglia activation via the regulation of parkin and p62 in microglia. The results obtained from this study will unveil the regulatory mechanisms of TSPO in neuroinflammation, thereby contribute to the anti-inflammatory therapeutic design for the treatment of neurodegernative diseases ⓒ 2016 DGIST
Table Of Contents
1. INTRODUCTION 1-- 1.1 Microglia 1-- 1.1.1Origin and distribution 1-- 1.1.2Microglia morphology and activation 2-- 1.2 Neuroinflammation 2-- 1.2.1 Microglia in neuroinflammation 2-- 1.2.2Neuroinflammation in neurodegenerative disease 3-- 1.3 TSPO 4-- 1.3.1Historical perspective and recent controversial topics 5-- 1.3.2 Structure and distribution 5-- 1.3.3 Function 5-- 1.3.4 Ligands 6-- 1.3.5 TSPO in neuroinflammation and neurodegenerative disease 6-- 1.4 Parkin 7-- 1.4.1 Parkin Structure and Function 7-- 1.4.2 Parkin and neuroinflammation in neurodegenerative diseases 8-- 2. Methods and Materials 9-- 2.1 Chemicals and reagents 9-- 2.2 Cell cultures 9-- 2.3 Nitrite assay 9-- 2.4 Enzyme-Linked Immunosorbent Assay (ELISA) 10-- 2.5 NF-κB luciferase reporter assay 10-- 2.6 Western blot Analysis 10-- 2.7 Immunoprecipitation 11-- 2.8 DNA transfection and knockdown 11-- 2.9 Statistical Analyses 12-- 3. Results 13-- 3.1 Translocator Protein 18 kDa (TSPO) is a negative regulator in neuroinflammation in microglia 13-- 3.2 TSPO suppresses MAPK activation and NF-κB activity in microglia 13-- 3.3 Parkin suppresses neuroinflammation in microglia 14-- 3.4 TSPO modulates neuroinflammation via Parkin in microglia 15-- 3.5 TSPO and Parkin regulate inflammation via autophagy 16-- 3.6 Parkin R275W mutant is associated with the regulation of inflammation in microglia 16-- 4. Discussion 18-- 5. Figure legends 21-- 6. Figures 26-- References 44--
URI
http://dgist.dcollection.net/jsp/common/DcLoOrgPer.jsp?sItemId=000002229068
http://hdl.handle.net/20.500.11750/1443
DOI
10.22677/thesis.2229068
Degree
Master
Department
Brain and Cognitive Sciences
University
DGIST
Files:
Collection:
Brain and Cognitive SciencesThesesMaster


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