PMID- 37038192 OWN - NLM STAT- MEDLINE DCOM- 20230412 LR - 20230413 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 20 IP - 1 DP - 2023 Apr 10 TI - The cervical lymph node contributes to peripheral inflammation related to Parkinson's disease. PG - 93 LID - 10.1186/s12974-023-02770-5 [doi] LID - 93 AB - BACKGROUND: Peripheral inflammation is an important feature of Parkinson's disease (PD). However, if and how CNS pathology is involved in the peripheral inflammation in PD remains to be fully investigated. Recently, the existence of meningeal lymphatics and its involvement in draining cerebral spinal fluid (CSF) to the cervical lymph node has been discovered. It is known that meningeal lymphatic dysfunction exists in idiopathic PD. The deep cervical lymph node (dCLN) substantially contributes to the drainage of the meningeal lymphatics. In addition, one of the lymphatics draining components, CSF, contains abundant alpha-synuclein (alpha-syn), a protein critically involved in PD pathogenesis and neuroinflammation. Thus, we began with exploring the possible structural and functional alterations of the dCLN in a PD mouse model (A53T mice) and investigated the role of pathological alpha-syn in peripheral inflammation and its potential underlying molecular mechanisms. METHODS: In this study, the transgenic mice (prnp-SNCA*A53T) which specifically overexpressed A53T mutant alpha-syn in CNS were employed as the PD animal model. Immunofluorescent and Hematoxylin and eosin staining were used to evaluate structure of dCLN. Inflammation in dCLNs as well as in bone-marrow-derived macrophages (BMDMs) was assessed quantitatively by measuring the mRNA and protein levels of typical inflammatory cytokines (including IL-1beta, IL-6 and TNF-alpha). Intra-cisterna magna injection, flow cytometric sorting and electrochemiluminescence immunoassays were applied to investigate the lymphatic drainage of alpha-syn from the CNS. RNA-seq and Western blot were used to explore how pathological alpha-syn mediated the inflammation in PD mice. RESULTS: The results unequivocally revealed substantially enlarged dCLNs, along with slow lymphatic flow, and increased inflammation in the dCLNs of A53T mice. Oligomeric alpha-syn drained from CSF potently activated macrophages in the dCLN via endoplasmic reticulum (ER) stress. Notably, inhibition of ER stress effectively suppressed peripheral inflammation in PD mice. CONCLUSIONS: Our findings indicate that lymph node enlargement is closely related to macrophage activation, induced by meningeal lymphatics draining oligomeric alpha-syn, and contributes to the peripheral inflammation in PD. In addition, ER stress is a potential therapeutic target to ameliorate PD pathogenesis. CI - (c) 2023. The Author(s). FAU - Liu, Zongran AU - Liu Z AD - Department of Pathology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310002, Zhejiang, China. AD - Department of Pathology, Peking University Health Science Center, Beijing, 100191, China. FAU - Huang, Yang AU - Huang Y AD - Department of Pathology, Peking University Health Science Center, Beijing, 100191, China. FAU - Wang, Xuejing AU - Wang X AD - Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China. AD - Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, 450052, Henan, China. FAU - Li, Jia-Yi AU - Li JY AD - Neural Plasticity and Repair Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden. AD - Institute of Health Sciences, China Medical University, Shenyang, 110122, Liaoning, China. FAU - Zhang, Can AU - Zhang C AD - Department of Pathology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310002, Zhejiang, China. FAU - Yang, Ying AU - Yang Y AD - Department of Pathology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310002, Zhejiang, China. rebecca_yang@zju.edu.cn. AD - Department of Pathology, Peking University Health Science Center, Beijing, 100191, China. rebecca_yang@zju.edu.cn. FAU - Zhang, Jing AU - Zhang J AD - Department of Pathology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310002, Zhejiang, China. jzhang1989@zju.edu.cn. AD - National Human Brain Bank for Health and Disease, Zhejiang University, Hangzhou, 310002, Zhejiang, China. jzhang1989@zju.edu.cn. LA - eng GR - 82001200/National Natural Science Foundation of China/ GR - 81571226/National Natural Science Foundation of China/ GR - LZ23H090002/Natural Science Foundation of Zhejiang Province/ PT - Journal Article DEP - 20230410 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (alpha-Synuclein) SB - IM MH - Mice MH - Animals MH - *Parkinson Disease/pathology MH - alpha-Synuclein/metabolism MH - Mice, Transgenic MH - Inflammation MH - Macrophages/metabolism MH - Lymph Nodes/pathology PMC - PMC10088204 OTO - NOTNLM OT - Cervical lymph node OT - Endoplasmic reticulum stress OT - Inflammation OT - Macrophage OT - Parkinson's disease OT - alpha-Synuclein COIS- The authors declare that they have no competing interests. EDAT- 2023/04/11 06:00 MHDA- 2023/04/12 06:42 PMCR- 2023/04/10 CRDT- 2023/04/10 23:48 PHST- 2022/10/04 00:00 [received] PHST- 2023/03/20 00:00 [accepted] PHST- 2023/04/12 06:42 [medline] PHST- 2023/04/10 23:48 [entrez] PHST- 2023/04/11 06:00 [pubmed] PHST- 2023/04/10 00:00 [pmc-release] AID - 10.1186/s12974-023-02770-5 [pii] AID - 2770 [pii] AID - 10.1186/s12974-023-02770-5 [doi] PST - epublish SO - J Neuroinflammation. 2023 Apr 10;20(1):93. doi: 10.1186/s12974-023-02770-5.