Celastrol Downmodulates Alpha-Synuclein-Specific T Cell Responses by Mediating Antigen Trafficking in Dendritic Cells

Ng，Lam1; Wang，Xiaohui1; Yang，Chuanbin2,3; Su，Chengfu2,4; Li，Min2,3; Cheung，Allen Ka Loon1

2022-03-02

10.3389/fimmu.2022.833515

Frontiers in Immunology   影响因子和分区

1664-3224

1664-3224

Parkinson’s Disease (PD) is a neurodegenerative disease that affects the elderly. It is associated with motor dysfunction due to the accumulation of misfolded or aggregated fibrillar alpha-synuclein (α-syn) in the mid-brain. Current treatments are mainly focused on relieving the symptoms but are accompanied by side effects and are limited in halting disease progression. Increasing evidence points to peripheral immune cells underlying disease development, especially T cells contributing to α-syn-related neuroinflammation in PD. The onset of these cells is likely mediated by dendritic cells (DCs), whose role in α-syn-specific responses remain less studied. Moreover, Traditional Chinese medicine (TCM)-derived compounds that are candidates to treat PD may alleviate DC-T cell-mediated immune responses. Therefore, our study focused on the role of DC in response to fibrillar α-syn and subsequent induction of antigen-specific T cell responses, and the effect of TCM Curcumin-analog C1 and Tripterygium wilfordii Hook F-derived Celastrol. We found that although fibrillar α-syn did not induce significant inflammatory or T cell-mediating cytokines, robust pro-inflammatory T cell responses were found by co-culturing fibrillar α-syn-pulsed DCs with α-syn-specific CD4 T cells. Celastrol, but not C1, reduced the onset of pro-inflammatory T cell differentiation, through promoting interaction of endosomal, amphisomal, and autophagic vesicles with fibrillar α-syn, which likely lead to its degradation and less antigen peptides available for presentation and T cell recognition. In conclusion, regulating the intracellular trafficking/processing of α-syn by DCs can be a potential approach to control the progression of PD, in which Celastrol is a potential candidate to accomplish this.

autophagy CD4+ T cell subsets Celastrol dendritic cell endo-lysosomal pathway Parkinson’s Disease α-synuclein

SCI

英语

通讯

Health and Medical Research Fund (HMRF)[18170032] ; Interdisciplinary Research Matching Scheme[RC-IRCs-1718-03] ; Hong Kong Government["HMRF17182541","HMRF17182551","GRF/HKBU12100618"] ; National Natural Science Foundation of China[81703487,81773926] ; Shenzhen Science and Technology Innovation Commission["JCYJ20180302174028790","JCYJ20180507184656626"] ; [FRG2/17-18/066] ; [SCI-17-18-01] ; [RC-SGT2/18-19/SCI/007]

Immunology

Immunology

WOS:000819924600001

FRONTIERS MEDIA SA

2-s2.0-85126779728

Scopus

1.Department of Biology,Faculty of Science,Hong Kong Baptist University,Kowloon Tong,Hong Kong
2.Center for Parkinson Disease Research,School of Chinese Medicine,Hong Kong Baptist University,Kowloon Tong,Hong Kong
3.Department of Geriatrics,Shenzhen People’s Hospital (The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology,Shenzhen,China
4.College of Pharmacy,Henan University of Chinese Medicine,Zhengzhou,China

Ng，Lam,Wang，Xiaohui,Yang，Chuanbin,et al. Celastrol Downmodulates Alpha-Synuclein-Specific T Cell Responses by Mediating Antigen Trafficking in Dendritic Cells[J]. Frontiers in Immunology,2022,13.

Ng，Lam,Wang，Xiaohui,Yang，Chuanbin,Su，Chengfu,Li，Min,&Cheung，Allen Ka Loon.(2022).Celastrol Downmodulates Alpha-Synuclein-Specific T Cell Responses by Mediating Antigen Trafficking in Dendritic Cells.Frontiers in Immunology,13.

Ng，Lam,et al."Celastrol Downmodulates Alpha-Synuclein-Specific T Cell Responses by Mediating Antigen Trafficking in Dendritic Cells".Frontiers in Immunology 13(2022).