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First published online February 12, 2021

Neuroinflammation in Parkinson’s Disease: Triggers, Mechanisms, and Immunotherapies

Abstract

Parkinson’s disease (PD) is a heterogeneous neurodegenerative disease involving multiple etiologies and pathogenesis, in which neuroinflammation is a common factor. Both preclinical experiments and clinical studies provide evidence for the involvement of neuroinflammation in the pathophysiology of PD, although there are a number of key issues related to neuroinflammatory processes in PD that remain to be addressed. In this review, we highlight the relationship between the common pathological mechanisms of PD and neuroinflammation, including aggregation of α-synuclein, genetic factors, mitochondrial dysfunction, and gut microbiome dysbiosis. We also describe the two positive feedback loops initiated in PD after the immune system is activated, and their role in the pathogenesis of PD. In addition, the interconnections and differences between the central and peripheral immune systems are discussed. Finally, we review the latest progress in immunotherapy research for PD patients, and propose future directions for clinical research.

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References

Acuña L, Hamadat S, Corbalán NS, González-Lizárraga F, Dos-Santos-Pereira M, Rocca J others. 2019. Rifampicin and its derivative rifampicin quinone reduce microglial inflammatory responses and neurodegeneration induced in vitro by α-synuclein fibrillary aggregates. Cells 8(8):776.
Agarwal S, Yadav A, Chaturvedi RK. 2017. Peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders. Biochem Biophys Res Commun 483(4):1166–77.
Ahmed I, Tamouza R, Delord M, Krishnamoorthy R, Tzourio C, Mulot C others. 2012. Association between Parkinson’s disease and the HLA-DRB1 locus. Mov Disord 27(9):1104–10.
Aliseychik MP, Andreeva TV, Rogaev EI. 2018. Immunogenetic factors of neurodegenerative diseases: the role of HLA class II. Biochemistry (Mosc) 83(9):1104–16.
Atashrazm F, Hammond D, Perera G, Dobson-Stone C, Mueller N, Pickford R others. 2018. Reduced glucocerebrosidase activity in monocytes from patients with Parkinson’s disease. Sci Rep 8(1):15446.
Baba Y, Kuroiwa A, Uitti RJ, Wszolek ZK, Yamada T. 2005. Alterations of T-lymphocyte populations in Parkinson disease. Parkinsonism Relat Disord 11(8):493–8.
Becher B, Spath S, Goverman J. 2017. Cytokine networks in neuroinflammation. Nat Rev Immunol 17(1):49–59.
Beilina A, Rudenko IN, Kaganovich A, Civiero L, Chau H, Kalia SK others. 2014. Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. Proc Natl Acad Sci U S A 111(7):2626–31.
Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH others. 2006. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38(5):515–7.
Benner EJ, Mosley RL, Destache CJ, Lewis TB, Jackson-Lewis V, Gorantla S others. 2004. Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A 101(25):9435–40.
Béraud D, Twomey M, Bloom B, Mittereder A, Ton V, Neitzke K others. 2011. α-Synuclein alters toll-like receptor expression. Front Neurosci 5:80.
Bhattacharya P, Budnick I, Singh M, Thiruppathi M, Alharshawi K, Elshabrawy H others. 2015. Dual role of GM-CSF as a pro-inflammatory and a regulatory cytokine: implications for immune therapy. J Interferon Cytokine Res 35(8):585–99.
Brakedal B, Flønes I, Reiter SF, Torkildsen Ø, Dölle C, Assmus J others. 2017. Glitazone use associated with reduced risk of Parkinson’s disease. Mov Disord 32(11):1594–9.
Brauer R, Bhaskaran K, Chaturvedi N, Dexter DT, Smeeth L, Douglas I. 2015. Glitazone treatment and incidence of Parkinson’s disease among people with diabetes: a retrospective cohort study. PLoS Med 12(7):e1001854.
Brochard V, Combadière B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V others. 2009. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119(1):182–92.
Brys M, Fanning L, Hung S, Ellenbogen A, Penner N, Yang M others. 2019. Randomized phase I clinical trial of anti-α-synuclein antibody BIIB054. Mov Disord 34(8):1154–63.
Bury AG, Pyle A, Elson JL, Greaves L, Morris CM, Hudson G others. 2017. Mitochondrial DNA changes in pedunculopontine cholinergic neurons in Parkinson disease. Ann Neurol 82(6):1016–21.
Bylicky MA, Mueller GP, Day RM. 2018. Mechanisms of endogenous neuroprotective effects of astrocytes in brain injury. Oxid Med Cell Longev 2018:6501031.
Cebrián C, Zucca FA, Mauri P, Steinbeck JA, Studer L, Scherzer CR others. 2014. MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat Commun 5:3633.
Chang D, Nalls MA, Hallgrímsdóttir IB, Hunkapiller J, van der Brug M, Cai F others. 2017. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat Genet 49(10):1511–6.
Chen J, Su P, Luo W, Chen J. 2018. Role of LRRK2 in manganese-induced neuroinflammation and microglial autophagy. Biochem Biophys Res Commun 498(1):171–7.
Chiu CC, Lu CS, Weng YH, Chen YL, Huang YZ, Chen RS others. 2019. PARK14 (D331Y) PLA2G6 causes early-onset degeneration of substantia nigra dopaminergic neurons by inducing mitochondrial dysfunction, ER stress, mitophagy impairment and transcriptional dysregulation in a knockin mouse model. Mol Neurobiol 56(6):3835–53.
Choi NM, Majumder P, Boss JM. 2011. Regulation of major histocompatibility complex class II genes. Curr Opin Immunol 23(1):81–7.
Chung YC, Shin WH, Baek JY, Cho EJ, Baik HH, Kim SR others. 2016. CB2 receptor activation prevents glial-derived neurotoxic mediator production, BBB leakage and peripheral immune cell infiltration and rescues dopamine neurons in the MPTP model of Parkinson’s disease. Exp Mol Med 48(1):e205.
Cirstea MS, Yu AC, Golz E, Sundvick K, Kliger D, Radisavljevic N others. 2020. Microbiota composition and metabolism are associated with gut function in Parkinson’s disease. Mov Disord 35(7):1208–17.
Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH others. 2006. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441(7097):1162–6.
Connolly JG, Bykov K, Gagne JJ. 2015. Thiazolidinediones and Parkinson disease: a cohort study. Am J Epidemiol 182(11):936–44.
Cookson MR. 2016. Cellular functions of LRRK2 implicate vesicular trafficking pathways in Parkinson’s disease. Biochem Soc Trans 44(6):1603–10.
Cose S, Brammer C, Khanna KM, Masopust D, Lefrançois L. 2006. Evidence that a significant number of naive T cells enter non-lymphoid organs as part of a normal migratory pathway. Eur J Immunol 36(6):1423–33.
Couch Y, Alvarez-Erviti L, Sibson NR, Wood MJ, Anthony DC. 2011. The acute inflammatory response to intranigral α-synuclein differs significantly from intranigral lipopolysaccharide and is exacerbated by peripheral inflammation. J Neuroinflammation 8:166.
Daniele SG, Béraud D, Davenport C, Cheng K, Yin H, Maguire-Zeiss KA. 2015. Activation of MyD88-dependent TLR1/2 signaling by misfolded α-synuclein, a protein linked to neurodegenerative disorders. Sci Signal 8(376):ra45.
Dasu MR, Riosvelasco AC, Jialal I. 2009. Candesartan inhibits toll-like receptor expression and activity both in vitro and in vivo. Atherosclerosis 202(1):76–83.
de Leon MJ, Li Y, Okamura N, Tsui WH, Saint-Louis LA, Glodzik L others. 2017. Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET. J Nucl Med 58(9):1471–6.
Dehmer T, Heneka MT, Sastre M, Dichgans J, Schulz JB. 2004. Protection by pioglitazone in the MPTP model of Parkinson’s disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation. J Neurochem 88(2):494–501.
Delgado M, Chorny A, Gonzalez-Rey E, Ganea D. 2005. Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo. J Leukoc Biol 78(6):1327–38.
Deng H, Wang P, Jankovic J. 2018. The genetics of Parkinson disease. Ageing Res Rev 42:72–85.
Depboylu C, Stricker S, Ghobril JP, Oertel WH, Priller J, Höglinger GU. 2012. Brain-resident microglia predominate over infiltrating myeloid cells in activation, phagocytosis and interaction with T-lymphocytes in the MPTP mouse model of Parkinson disease. Exp Neurol 238(2):183–91.
Devi L, Raghavendran V, Prabhu BM, Avadhani NG, Anandatheerthavarada HK. 2008. Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem 283(14):9089–100.
Du L, Zhang Y, Chen Y, Zhu J, Yang Y, Zhang HL. 2017. Role of microglia in neurological disorders and their potentials as a therapeutic target. Mol Neurobiol 54(10):7567–84.
Duffy MF, Collier TJ, Patterson JR, Kemp CJ, Luk KC, Tansey MG others. 2018. Correction to: Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration. J Neuroinflammation 15(1):169.
Erny D, Hrabě de, Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E others. 2015. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18(7):965–77.
Faucheux BA, Bonnet AM, Agid Y, Hirsch EC. 1999. Blood vessels change in the mesencephalon of patients with Parkinson’s disease. Lancet 353(9157):981–2.
Fellner L, Irschick R, Schanda K, Reindl M, Klimaschewski L, Poewe W others. 2013. Toll-like receptor 4 is required for α-synuclein dependent activation of microglia and astroglia. Glia 61(3):349–60.
Fiszer U, Mix E, Fredrikson S, Kostulas V, Link H. 1994. Parkinson’s disease and immunological abnormalities: increase of HLA-DR expression on monocytes in cerebrospinal fluid and of CD45RO+ T cells in peripheral blood. Acta Neurol Scand 90(3):160–6.
Florenzano F, Bentivoglio M. 2000. Degranulation, density, and distribution of mast cells in the rat thalamus: a light and electron microscopic study in basal conditions and after intracerebroventricular administration of nerve growth factor. J Comp Neurol 424(4):651–69.
Foo JN, Chung SJ, Tan LC, Liany H, Ryu HS, Hong M others. 2016. Linking a genome-wide association study signal to a LRRK2 coding variant in Parkinson’s disease. Mov Disord 31(4):484–7.
Foo JN, Tan LC, Irwan ID, Au WL, Low HQ, Prakash KM others. 2017. Genome-wide association study of Parkinson’s disease in East Asians. Hum Mol Genet 26(1):226–32.
Games D, Valera E, Spencer B, Rockenstein E, Mante M, Adame A others. 2014. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson’s disease-like models. J Neurosci 34(28):9441–54.
Gao X, Chen H, Schwarzschild MA, Ascherio A. 2011. Use of ibuprofen and risk of Parkinson disease. Neurology 76(10):863–9.
Gendelman HE, Zhang Y, Santamaria P, Olson KE, Schutt CR, Bhatti D others. 2017. Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson’s disease trial. NPJ Parkinsons Dis 3:10.
Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A others. 2006. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis 21(2):404–12.
Goldzweig O, Hashkes PJ. 2011. Abatacept in the treatment of polyarticular JIA: development, clinical utility, and place in therapy. Drug Des Devel Ther 5:61–70.
Gordon R, Albornoz EA, Christie DC, Langley MR, Kumar V, Mantovani S others. 2018. Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med 10(465):eaah4066.
Grazioli S, Pugin J. 2018. Mitochondrial damage-associated molecular patterns: from inflammatory signaling to human diseases. Front Immunol 9:832.
Greenfield EA, Nguyen KA, Kuchroo VK. 1998. CD28/B7 costimulation: a review. Crit Rev Immunol 18(5):389–418.
Grozdanov V, Bousset L, Hoffmeister M, Bliederhaeuser C, Meier C, Madiona K others. 2019. Increased immune activation by pathologic α-synuclein in Parkinson’s disease. Ann Neurol 86(4):593–606.
Guo M, Wang J, Zhao Y, Feng Y, Han S, Dong Q others. 2020. Microglial exosomes facilitate α-synuclein transmission in Parkinson’s disease. Brain 143(5):1476–97.
Hammer J, Valsasnini P, Tolba K, Bolin D, Higelin J, Takacs B others. 1993. Promiscuous and allele-specific anchors in HLA-DR-binding peptides. Cell 74(1):197–203.
Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D others. 2010. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet 42(9):781–5.
Harms AS, Cao S, Rowse AL, Thome AD, Li X, Mangieri LR others. 2013. MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J Neurosci 33(23):9592–600.
Harms AS, Thome AD, Yan Z, Schonhoff AM, Williams GP, Li X others. 2018. Peripheral monocyte entry is required for alpha-Synuclein induced inflammation and neurodegeneration in a model of Parkinson disease. Exp Neurol 300:179–87.
Hayes GM, Woodroofe MN, Cuzner ML. 1987. Microglia are the major cell type expressing MHC class II in human white matter. J Neurol Sci 80(1):25–37.
Henry AG, Aghamohammadzadeh S, Samaroo H, Chen Y, Mou K, Needle E others. 2015. Pathogenic LRRK2 mutations, through increased kinase activity, produce enlarged lysosomes with reduced degradative capacity and increase ATP13A2 expression. Hum Mol Genet 24(21):6013–28.
Hirsch EC, Hunot S. 2009. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol 8(4):382–97.
Hirsch EC, Standaert DG. 2020. Ten unsolved questions about neuroinflammation in Parkinson’s disease. Mov Disord. Epub May 1.
Hongge L, Kexin G, Xiaojie M, Nian X, Jinsha H. 2015. The role of LRRK2 in the regulation of monocyte adhesion to endothelial cells. J Mol Neurosci 55(1):233–9.
Hu X, Ivashkiv LB. 2009. Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases. Immunity 31(4):539–50.
Hughes CD, Choi ML, Ryten M, Hopkins L, Drews A, Botía JA others. 2019. Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis. Acta Neuropathol 137(1):103–20.
Iba M, Kim C, Sallin M, Kwon S, Verma A, Overk C others. 2020. Neuroinflammation is associated with infiltration of T cells in Lewy body disease and α-synuclein transgenic models. J Neuroinflammation 17(1):214.
Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA others. 2012. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4(147):147ra111.
Irrcher I, Aleyasin H, Seifert EL, Hewitt SJ, Chhabra S, Phillips M others. 2010. Loss of the Parkinson’s disease-linked gene DJ-1 perturbs mitochondrial dynamics. Hum Mol Genet 19(19):3734–46.
Janelidze S, Lindqvist D, Francardo V, Hall S, Zetterberg H, Blennow K others. 2015. Increased CSF biomarkers of angiogenesis in Parkinson disease. Neurology 85(21):1834–42.
Jankovic J. 2019. Pathogenesis-targeted therapeutic strategies in Parkinson’s disease. Mov Disord 34(1):41–4.
Jankovic J, Goodman I, Safirstein B, Marmon TK, Schenk DB, Koller M others. 2018. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-α-synuclein monoclonal antibody, in patients with Parkinson disease: a randomized clinical trial. JAMA Neurol 75(10):1206–14.
Javed H, Azimullah S, Haque ME, Ojha SK. 2016. Cannabinoid type 2 (CB2) receptors activation protects against oxidative stress and neuroinflammation associated dopaminergic neurodegeneration in rotenone model of Parkinson’s disease. Front Neurosci 10:321.
Jimenez-Ferrer I, Bäckström F, Dueñas-Rey A, Jewett M, Boza-Serrano A, Luk KC others. 2021. The MHC class II transactivator modulates seeded alpha-synuclein pathology and dopaminergic neurodegeneration in an in vivo rat model of Parkinson’s disease. Brain Behav Immun 91:369–82.
Johnson ME, Stecher B, Labrie V, Brundin L, Brundin P. 2019. Triggers, facilitators, and aggravators: redefining Parkinson’s disease pathogenesis. Trends Neurosci 42(1):4–13.
Kalia LV, Lang AE. 2015. Parkinson’s disease. Lancet 386(9996):896–912.
Kamp F, Exner N, Lutz AK, Wender N, Hegermann J, Brunner B others. 2010. Inhibition of mitochondrial fusion by α-synuclein is rescued by PINK1, Parkin and DJ-1. EMBO J 29(20):3571–89.
Kempuraj D, Ahmed ME, Selvakumar GP, Thangavel R, Raikwar SP, Zaheer SA others. 2020. Mast cell activation, neuroinflammation, and tight junction protein derangement in acute traumatic brain injury. Mediators Inflamm 2020:4243953.
Kempuraj D, Selvakumar GP, Zaheer S, Thangavel R, Ahmed ME, Raikwar S others. 2018. Cross-talk between glia, neurons and mast cells in neuroinflammation associated with Parkinson’s disease. J Neuroimmune Pharmacol 13(1):100–12.
Keshavarzian A, Green SJ, Engen PA, Voigt RM, Naqib A, Forsyth CB others. 2015. Colonic bacterial composition in Parkinson’s disease. Mov Disord 30(10):1351–60.
Kim BW, Koppula S, Kumar H, Park JY, Kim IW, More SV others. 2015. α-Asarone attenuates microglia-mediated neuroinflammation by inhibiting NF kappa B activation and mitigates MPTP-induced behavioral deficits in a mouse model of Parkinson’s disease. Neuropharmacology 97:46–57.
Kim C, Ho DH, Suk JE, You S, Michael S, Kang J others. 2013. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Commun 4:1562.
Kim C, Spencer B, Rockenstein E, Yamakado H, Mante M, Adame A others. 2018. Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation. Mol Neurodegener 13(1):43.
Kim JS, Ryu SY, Yun I, Kim WJ, Lee KS, Park JW others. 2006. 1alpha,25-Dihydroxyvitamin D(3) protects dopaminergic neurons in rodent models of Parkinson’s disease through inhibition of microglial activation. J Clin Neurol 2(4):252–7.
Kim S, Kwon SH, Kam TI, Panicker N, Karuppagounder SS, Lee S others. 2019. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron 103(4):627–641.e7.
King E, Thomas A. 2017. Systemic inflammation in Lewy body diseases: a systematic review. Alzheimer Dis Assoc Disord 31(4):346–56.
Kirk AD, Harlan DM, Armstrong NN, Davis TA, Dong Y, Gray GS others. 1997. CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci U S A 94(16):8789–94.
Kluss JH, Mamais A, Cookson MR. 2019. LRRK2 links genetic and sporadic Parkinson’s disease. Biochem Soc Trans 47(2):651–61.
Korhonen R, Moilanen E. 2009. Abatacept, a novel CD80/86-CD28 T cell co-stimulation modulator, in the treatment of rheumatoid arthritis. Basic Clin Pharmacol Toxicol 104(4):276–84.
Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J, Willemsen AT others. 2005. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol 57(2):176–9.
Kosloski LM, Kosmacek EA, Olson KE, Mosley RL, Gendelman HE. 2013. GM-CSF induces neuroprotective and anti-inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxicated mice. J Neuroimmunol 265(1–2): 1–10.
Kouli A, Camacho M, Allinson K, Williams-Gray CH. 2020. Neuroinflammation and protein pathology in Parkinson’s disease dementia. Acta Neuropathol Commun 8(1):211.
Kuhn C, Weiner HL. 2016. Therapeutic anti-CD3 monoclonal antibodies: from bench to bedside. Immunotherapy 8(8):889–906.
Larsen CP, Pearson TC, Adams AB, Tso P, Shirasugi N, Strobert E others. 2005. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant 5(3):443–53.
Lee HJ, Suk JE, Bae EJ, Lee SJ. 2008. Clearance and deposition of extracellular alpha-synuclein aggregates in microglia. Biochem Biophys Res Commun 372(3):423–8.
Licker V, Turck N, Kövari E, Burkhardt K, Côte M, Surini-Demiri M others. 2014. Proteomic analysis of human substantia nigra identifies novel candidates involved in Parkinson’s disease pathogenesis. Proteomics 14(6):784–94.
Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L others. 2017. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638):481–7.
Lin CH, Chen CC, Chiang HL, Liou JM, Chang CM, Lu TP others. 2019. Altered gut microbiota and inflammatory cytokine responses in patients with Parkinson’s disease. J Neuroinflammation 16(1):129.
Lindestam Arlehamn CS, Dhanwani R, Pham J, Kuan R, Frazier A, Rezende Dutra J others. 2020. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease. Nat Commun 11(1):1875.
Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. 1991. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 174(3):561–9.
Linsley PS, Greene JL, Tan P, Bradshaw J, Ledbetter JA, Anasetti C others. 1992. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med 176(6):1595–604.
Liu Z, Huang Y, Cao BB, Qiu YH, Peng YP. 2017a. Th17 cells induce dopaminergic neuronal death via LFA-1/ICAM-1 interaction in a mouse model of Parkinson’s disease. Mol Neurobiol 54(10):7762–76.
Liu Y, Xie X, Xia LP, Lv H, Lou F, Ren Y others. 2017b. Peripheral immune tolerance alleviates the intracranial lipopolysaccharide injection-induced neuroinflammation and protects the dopaminergic neurons from neuroinflammation-related neurotoxicity. J Neuroinflammation 14(1):223.
Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD others. 2015. Structural and functional features of central nervous system lymphatic vessels. Nature 523(7560):337–41.
Luth ES, Stavrovskaya IG, Bartels T, Kristal BS, Selkoe DJ. 2014. Soluble, prefibrillar α-synuclein oligomers promote complex I-dependent, Ca2+-induced mitochondrial dysfunction. J Biol Chem 289(31):21490–507.
Mandler M, Valera E, Rockenstein E, Mante M, Weninger H, Patrick C others. 2015. Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol Neurodegener 10:10.
Mandler M, Valera E, Rockenstein E, Weninger H, Patrick C, Adame A others. 2014. Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials. Acta Neuropathol 127(6):861–79.
Matheoud D, Sugiura A, Bellemare-Pelletier A, Laplante A, Rondeau C, Chemali M others. 2016. Parkinson’s disease-related proteins PINK1 and parkin repress mitochondrial antigen presentation. Cell 166(2):314–27.
McGeer PL, Itagaki S, Boyes BE, McGeer EG. 1988. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38(8):1285–91.
Mishra A, Singh S, Tiwari V, Chaturvedi S, Wahajuddin M, Shukla S. 2019. Dopamine receptor activation mitigates mitochondrial dysfunction and oxidative stress to enhance dopaminergic neurogenesis in 6-OHDA lesioned rats: a role of Wnt signalling. Neurochem Int 129:104463.
Morsch M, Radford R, Lee A, Don EK, Badrock AP, Hall TE others. 2015. In vivo characterization of microglial engulfment of dying neurons in the zebrafish spinal cord. Front Cell Neurosci 9:321.
Mortiboys H, Johansen KK, Aasly JO, Bandmann O. 2010. Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2. Neurology 75(22):2017–20.
Mullin S, Schapira AH. 2015. Pathogenic mechanisms of neurodegeneration in Parkinson disease. Neurol Clin 33(1):1–17.
Nagatsu T, Mogi M, Ichinose H, Togari A. 2000. Changes in cytokines and neurotrophins in Parkinson’s disease. J Neural Transm Suppl (60):277–90.
Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D others. 2019. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol 18(12):1091–102.
Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M others. 2011. Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet 377(9766):641–9.
Navarrete F, García-Gutiérrez MS, Aracil-Fernández A, Lanciego JL, Manzanares J. 2018. Cannabinoid CB1 and CB2 receptors, and monoacylglycerol lipase gene expression alterations in the basal ganglia of patients with Parkinson’s disease. Neurotherapeutics 15(2):459–69.
Neniskyte U, Vilalta A, Brown GC. 2014. Tumour necrosis factor alpha-induced neuronal loss is mediated by microglial phagocytosis. FEBS Lett 588(17):2952–6.
Nissen SK, Ferreira SA, Nielsen MC, Schulte C, Shrivastava K, Hennig D others. 2020. Soluble CD163 changes indicate monocyte association with cognitive deficits in Parkinson’s disease. Mov Disord. Epub Dec 17.
Nissen SK, Shrivastava K, Schulte C, Otzen DE, Goldeck D, Berg D others. 2019. Alterations in blood monocyte functions in Parkinson’s disease. Mov Disord 34(11):1711–21.
Noelker C, Morel L, Osterloh A, Alvarez-Fischer D, Lescot T, Breloer M others. 2014. Heat shock protein 60: an endogenous inducer of dopaminergic cell death in Parkinson disease. J Neuroinflammation 11:86.
Obeso JA, Stamelou M, Goetz CG, Poewe W, Lang AE, Weintraub D others. 2017. Past, present, and future of Parkinson’s disease: a special essay on the 200th anniversary of the shaking palsy. Mov Disord 32(9):1264–310.
Olson KE, Bade AN, Schutt CR, Dong J, Shandler SJ, Boska MD others. 2016. Manganese-enhanced magnetic resonance imaging for detection of vasoactive intestinal peptide receptor 2 agonist therapy in a model of Parkinson’s disease. Neurotherapeutics 13(3):635–46.
Orihuela R, McPherson CA, Harry GJ. 2016. Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173(4):649–65.
Panicker N, Sarkar S, Harischandra DS, Neal M, Kam TI, Jin H others. 2019. Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia. J Exp Med 216(6):1411–30.
Parashar A, Udayabanu M. 2017. Gut microbiota: implications in Parkinson’s disease. Parkinsonism Relat Disord 38:1–7.
Penaranda C, Tang Q, Bluestone JA. 2011. Anti-CD3 therapy promotes tolerance by selectively depleting pathogenic cells while preserving regulatory T cells. J Immunol 187(4):2015–22.
Peter I, Dubinsky M, Bressman S, Park A, Lu C, Chen N others. 2018. Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease. JAMA Neurol 75(8):939–46.
Prasad KV, Cai YC, Raab M, Duckworth B, Cantley L, Shoelson SE others. 1994. T-cell antigen CD28 interacts with the lipid kinase phosphatidylinositol 3-kinase by a cytoplasmic Tyr(P)-Met-Xaa-Met motif. Proc Natl Acad Sci U S A 91(7):2834–8.
Qin H, Buckley JA, Li X, Liu Y, Fox TH 3rd, Meares GP others. 2016. Inhibition of the JAK/STAT pathway protects against α-synuclein-induced neuroinflammation and dopaminergic neurodegeneration. J Neurosci 36(18):5144–59.
Racette BA, Gross A, Vouri SM, Camacho-Soto A, Willis AW, Searles Nielsen S. 2018. Immunosuppressants and risk of Parkinson disease. Ann Clin Transl Neurol 5(7):870–5.
Ransohoff RM. 2016. A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 19(8):987–91.
Reynolds AD, Stone DK, Mosley RL, Gendelman HE. 2009. Nitrated α-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets. J Immunol 182(7):4137–49.
Ringstad G, Vatnehol SAS, Eide PK. 2017. Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain 140(10):2691–705.
Rochfort KD, Collins LE, Murphy RP, Cummins PM. 2014. Downregulation of blood-brain barrier phenotype by proinflammatory cytokines involves NADPH oxidase-dependent ROS generation: consequences for interendothelial adherens and tight junctions. PLoS One 9(7):e101815.
Rostami J, Fotaki G, Sirois J, Mzezewa R, Bergström J, Essand M others. 2020. Astrocytes have the capacity to act as antigen-presenting cells in the Parkinson’s disease brain. J Neuroinflammation 17(1):119.
Russo I, Kaganovich A, Ding J, Landeck N, Mamais A, Varanita T others. 2019. Transcriptome analysis of LRRK2 knock-out microglia cells reveals alterations of inflammatory- and oxidative stress-related pathways upon treatment with α-synuclein fibrils. Neurobiol Dis 129:67–78.
Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE others. 2016. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167(6):1469–1480.e12.
Sarkar S, Dammer EB, Malovic E, Olsen AL, Raza SA, Gao T others. 2020. Molecular signatures of neuroinflammation induced by α-synuclein aggregates in microglial cells. Front Immunol 11:33.
Saunders JA, Estes KA, Kosloski LM, Allen HE, Dempsey KM, Torres-Russotto DR others. 2012. CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson’s disease. J Neuroimmune Pharmacol 7(4):927–38.
Savitt D, Jankovic J. 2019. Targeting α-synuclein in Parkinson’s disease: progress towards the development of disease-modifying therapeutics. Drugs 79(8):797–810.
Schreck R, Rieber P, Baeuerle PA. 1991. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J 10(8):2247–58.
Schröder JB, Pawlowski M, Meyer Zu, Hörste G, Gross CC, Wiendl H, Meuth SG others. 2018. Immune cell activation in the cerebrospinal fluid of patients with Parkinson’s disease. Front Neurol 9:1081.
Schutt CR, Gendelman HE, Mosley RL. 2018. Tolerogenic bone marrow-derived dendritic cells induce neuroprotective regulatory T cells in a model of Parkinson’s disease. Mol Neurodegener 13(1):26.
Schwiertz A, Spiegel J, Dillmann U, Grundmann D, Bürmann J, Faßbender K others. 2018. Fecal markers of intestinal inflammation and intestinal permeability are elevated in Parkinson’s disease. Parkinsonism Relat Disord 50:104–7.
Shao W, Zhang SZ, Tang M, Zhang XH, Zhou Z, Yin YQ others. 2013. Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin. Nature 494(7435):90–4.
Sliter DA, Martinez J, Hao L, Chen X, Sun N, Fischer TD others. 2018. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561(7722):258–62.
Sommer A, Marxreiter F, Krach F, Fadler T, Grosch J, Maroni M others. 2018. Th17 lymphocytes induce neuronal cell death in a human iPSC-based model of Parkinson’s disease. Cell Stem Cell 23(1):123–131.e6.
Steger M, Tonelli F, Ito G, Davies P, Trost M, Vetter M others. 2016. Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife 5.
Su X, Maguire-Zeiss KA, Giuliano R, Prifti L, Venkatesh K, Federoff HJ. 2008. Synuclein activates microglia in a model of Parkinson’s disease. Neurobiol Aging 29(11):1690–701.
Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J others. 2017. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature 546(7660):656–61.
Swanson CR, Joers V, Bondarenko V, Brunner K, Simmons HA, Ziegler TE others. 2011. The PPAR-γ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys. J Neuroinflammation 8:91.
Takeda K, Akira S. 2004. TLR signaling pathways. Semin Immunol 16(1):3–9.
Terada T, Yokokura M, Yoshikawa E, Futatsubashi M, Kono S, Konishi T others. 2016. Extrastriatal spreading of microglial activation in Parkinson’s disease: a positron emission tomography study. Ann Nucl Med 30(8):579–87.
Theodore S, Cao S, McLean PJ, Standaert DG. 2008. Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J Neuropathol Exp Neurol 67(12):1149–58.
Turkheimer FE, Rizzo G, Bloomfield PS, Howes O, Zanotti-Fregonara P, Bertoldo A others. 2015. The methodology of TSPO imaging with positron emission tomography. Biochem Soc Trans 43(4):586–92.
Vincenti F, Blancho G, Durrbach A, Friend P, Grinyo J, Halloran PF others. 2010. Five-year safety and efficacy of belatacept in renal transplantation. J Am Soc Nephrol 21(9):1587–96.
Volpicelli-Daley L, Brundin P. 2018. Prion-like propagation of pathology in Parkinson disease. Handb Clin Neurol 153:321–35.
Wada K, Arai H, Takanashi M, Fukae J, Oizumi H, Yasuda T others. 2006. Expression levels of vascular endothelial growth factor and its receptors in Parkinson’s disease. Neuroreport 17(7):705–9.
Waisman A, Johann L. 2018. Antigen-presenting cell diversity for T cell reactivation in central nervous system autoimmunity. J Mol Med (Berl) 96(12):1279–92.
Wang S, Jing H, Yang H, Liu Z, Guo H, Chai L others. 2015. Tanshinone I selectively suppresses pro-inflammatory genes expression in activated microglia and prevents nigrostriatal dopaminergic neurodegeneration in a mouse model of Parkinson’s disease. J Ethnopharmacol 164:247–55.
Wang Y, Sha H, Zhou L, Chen Y, Zhou Q, Dong H others. 2020. The mast cell is an early activator of lipopolysaccharide-induced neuroinflammation and blood-brain barrier dysfunction in the hippocampus. Mediators Inflamm 2020:8098439.
Weihofen A, Liu Y, Arndt JW, Huy C, Quan C, Smith BA others. 2019. Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson’s disease models. Neurobiol Dis 124:276–88.
Wijeyekoon RS, Kronenberg-Versteeg D, Scott KM, Hayat S, Jones JL, Clatworthy MR others. 2018. Monocyte function in Parkinson’s disease and the impact of autologous serum on phagocytosis. Front Neurol 9:870.
Wijeyekoon RS, Moore SF, Farrell K, Breen DP, Barker RA, Williams-Gray CH. 2020. Cerebrospinal fluid cytokines and neurodegeneration-associated proteins in Parkinson’s disease. Mov Disord 35(6):1062–66.
Williams GP, Schonhoff AM, Jurkuvenaite A, Thome AD, Standaert DG, Harms AS. 2018. Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson’s disease. J Neuroinflammation 15(1):244.
Wissemann WT, Hill-Burns EM, Zabetian CP, Factor SA, Patsopoulos N, Hoglund B others. 2013. Association of Parkinson disease with structural and regulatory variants in the HLA region. Am J Hum Genet 93(5):984–93.
Witoelar A, Jansen IE, Wang Y, Desikan RS, Gibbs JR, Blauwendraat C others. 2017. Genome-wide pleiotropy between Parkinson disease and autoimmune diseases. JAMA Neurol 74(7):780–92.
Yamasaki R, Lu H, Butovsky O, Ohno N, Rietsch AM, Cialic R others. 2014. Differential roles of microglia and monocytes in the inflamed central nervous system. J Exp Med 211(8):1533–49.
Yun SP, Kam TI, Panicker N, Kim S, Oh Y, Park JS others. 2018. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat Med 24(7):931–8.
Zhang Q, Itagaki K, Hauser CJ. 2010. Mitochondrial DNA is released by shock and activates neutrophils via p38 map kinase. Shock 34(1):55–9.
Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML others. 2005. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 19(6):533–42.
Zhou P, Homberg JR, Fang Q, Wang J, Li W, Meng X others. 2019. Histamine-4 receptor antagonist JNJ7777120 inhibits pro-inflammatory microglia and prevents the progression of Parkinson-like pathology and behaviour in a rat model. Brain Behav Immun 76:61–73.
Zhou R, Yazdi AS, Menu P, Tschopp J. 2011. A role for mitochondria in NLRP3 inflammasome activation. Nature 469(7329):221–5.

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Article first published online: February 12, 2021
Issue published: August 2022

Keywords

  1. Parkinson’s disease
  2. neuroinflammation
  3. immunotherapies
  4. α-synuclein
  5. microglia

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PubMed: 33576313

Authors

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Tai Wang*
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
The Academy of Medical Sciences of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Changhe Shi*
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Institute of Neuroscience, Zhengzhou University, Zhengzhou, Henan, China
Haiyang Luo*
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
The Academy of Medical Sciences of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Huimin Zheng
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
The Academy of Medical Sciences of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Liyuan Fan
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
The Academy of Medical Sciences of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Mibo Tang
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
The Academy of Medical Sciences of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Yun Su
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
The Academy of Medical Sciences of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Jing Yang
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Institute of Neuroscience, Zhengzhou University, Zhengzhou, Henan, China
Chengyuan Mao
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
The Academy of Medical Sciences of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
Yuming Xu
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
Institute of Neuroscience, Zhengzhou University, Zhengzhou, Henan, China

Notes

Yuming Xu and Chengyuan Mao, Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Jian-she East Road, Zhengzhou, Henan 450000, China. Emails: [email protected]; [email protected]
*
These authors contributed equally to this article.

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