DAP12 and CD11b contribute to the microglial-induced death of dopaminergic neurons in vitro but not in vivo in the MPTP mouse model of Parkinson’s disease

Journal of Neuroinflammation

Stéphane Hunot²  Alain Bessis¹  Etienne C Hirsch²  Daniel Alvarez-Fischer³  Catherine Béchade¹  Yann Monnet²  Kiyoka Kinugawa⁴ 

[1] CNRS, UMR 8197, Paris F-75005, France;INSERM, UMR_S975, CRICM, Paris F-75013, France;Institute of Neurogenetics, University of Lübeck, Lübeck, Germany;Assistance Publique-Hôpitaux de Paris (AP-HP), Functional Explorations Unit of the Elderly, Charles Foix Hospital, Ivry-sur-Seine F-94200, France

关键词: MPTP;    Parkinson’s disease;    Dopaminergic neuron;    Microglia;    CD11b;    DAP12;   

Others  :  1152621
DOI  :  10.1186/1742-2094-10-82

 received in 2012-12-19, accepted in 2013-07-02,  发布年份 2013

【 摘 要 】

Background

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a loss of dopaminergic neurons (DN) in the substantia nigra (SN). Several lines of evidence suggest that apoptotic cell death of DN is driven in part by non-cell autonomous mechanisms orchestrated by microglial cell-mediated inflammatory processes. Although the mechanisms and molecular network underlying this deleterious cross-talk between DN and microglial cells remain largely unknown, previous work indicates that, upon DN injury, activation of the β2 integrin subunit CD11b is required for microglia-mediated DN cell death. Interestingly, during brain development, the CD11b integrin is also involved in microglial induction of neuronal apoptosis and has been shown to act in concert with the DAP12 immunoreceptor. Whether such a developmental CD11b/DAP12 pathway could be reactivated in a pathological context such as PD and play a role in microglia-induced DN cell death is a tantalizing hypothesis that we wished to test in this study.

Methods

To test the possibility that DAP12 could be involved in microglia-associated DN injury, we used both in vitro and in vivo toxin-based experimental models of PD recapitulating microglial-mediated non-cell autonomous mechanisms of DN cell death. In vitro, enriched mesencephalic neuronal/microglial co-cultures were exposed to the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+) whereas in vivo, mice were administrated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) according to acute or subchronic mode. Mice deficient for DAP12 or CD11b were used to determine the pathological function of the CD11b/DAP12 pathway in our disease models.

Results

Our results show that DAP12 and CD11b partially contribute to microglia-induced DN cell death in vitro. Yet, in vivo, mice deficient for either of these factors develop similar neuropathological alterations as their wild-type counterparts in two different MPTP mouse models of PD.

Conclusion

Overall, our data suggest that DAP12 and CD11b contribute to microglial-induced DN cell death in vitro but not in vivo in the MPTP mouse model of PD. Therefore, the CD11b/DAP12 pathway may not be considered as a promising therapeutic target for PD.

【 授权许可】

   
2013 Kinugawa et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 9.

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【 参考文献 】

• [1]Hirsch EC, Hunot S: Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol 2009, 8:382-397.
• [2]Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila M, McAuliffe WG, Dawson VL, Dawson TM, Przedborski S: Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 1999, 5:1403-1409.
• [3]Wu DC, Teismann P, Tieu K, Vila M, Jackson-Lewis V, Ischiropoulos H, Przedborski S: NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Proc Natl Acad Sci USA 2003, 100:6145-6150.
• [4]Pei Z, Pang H, Qian L, Yang S, Wang T, Zhang W, Wu X, Dallas S, Wilson B, Reece JM, Miller DS, Hong JS, Block ML: MAC1 mediates LPS-induced production of superoxide by microglia: the role of pattern recognition receptors in dopaminergic neurotoxicity. Glia 2007, 73:259-277.
• [5]Hu X, Zhang D, Pang H, Caudle WM, Li Y, Gao H, Liu Y, Qian L, Wilson B, Di Monte DA, Ali SF, Zhang J, Block ML, Hong JS: Macrophage antigen complex-1 mediates reactive microgliosis and progressive dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. J Immunol 2008, 181:7194-7204.
• [6]Nathan C, Srimal S, Farber C, Sanchez E, Kabbash L, Asch A, Gailit J, Wright SD: Cytokine-induced respiratory burst of human neutrophils: dependence on extracellular matrix proteins and CD11/CD18 integrins. J Cell Biol 1989, 109:1341-1349.
• [7]Abram CL, Lowell CA: The expanding role for ITAM-based signaling pathways in immune cells. Sci STKE 2007, 13:re2.
• [8]Mócsai A, Abram CL, Jakus Z, Hu Y, Lanier LL, Lowell CA: Integrin signaling in neutrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs. Nat Immunol 2006, 7:1326-1333.
• [9]Wakselman S, Béchade C, Roumier A, Bernard D, Triller A, Bessis A: Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor. J Neurosci 2008, 28:8138-8143.
• [10]Satoh J, Tabunoki H, Ishida T, Yagishita S, Jinnai K, Futamura N, Kobayashi M, Toyoshima I, Yoshioka T, Enomoto K, Arai N, Arima K: Immunohistochemical characterization of microglia in Nasu-Hakola disease brains. Neuropathology 2011, 31:363-375.
• [11]Roumier A, Béchade C, Poncer JC, Smalla KH, Tomasello E, Vivier E, Gundelfinger ED, Triller A, Bessis A: Impaired synaptic function in the microglial KARAP/DAP12-deficient mouse. J Neurosci 2004, 24:11421-11428.
• [12]Tomasello E, Desmoulins PO, Chemin K, Guia S, Cremer H, Ortaldo J, Love P, Kaiserlian D, Vivier E: Combined natural killer cell and dendritic cell functional deficiency in KARAP/DAP12 loss-of-function mutant mice. Immunity 2000, 13:355-364.
• [13]Guerreiro S, Toulorge D, Hirsch E, Marien M, Sokoloff P, Michel PP: Paraxanthine, the primary metabolite of caffeine, provides protection against dopaminergic cell death via stimulation of ryanodine receptor channels. Mol Pharmacol 2008, 74:980-989.
• [14]Théry C, Chamak B, Mallat M: Cytotoxic effect of brain macrophages on developing. Eur J Neurosci 1991, 3:1155-1164.
• [15]Nolan T, Hands RE, Bustin SA: Quantification of mRNA using real-time RT-PCR. Nat Protocol 2006, 1:1559-1582.
• [16]Luster AD, Alon R, von Andrian UH: Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 2005, 6:1182-1190.
• [17]Zhang W, Qin L, Wang T, Wei SJ, Gao HM, Liu J, Wilson B, Liu B, Zhang W, Kim HC, Hong JS: 3-hydroxymorphinan is neurotrophic to dopaminergic neurons and is also neuroprotective against LPS-induced neurotoxicity. FASEB J 2005, 19:395-397.
• [18]Beck KD, Knusel B, Pasinetti G, Michel PP, Zawadzka H, Goldstein M, Hefti F: Tyrosine hydroxylase mRNA expression by dopaminergic neurons in culture: effect of 1-methyl-4-phenylpyridinium treatment. J Neurochem 1991, 57:527-532.
• [19]Bindokas VP, Jordán J, Lee CC, Miller RJ: Superoxide production in rat hippocampal neurons: selective imaging with hydroethidine. J Neurosci 1996, 16:1324-1336.
• [20]Dauer W, Przedborski S: Parkinson’s disease: mechanisms and models. Neuron 2003, 39:889-909.
• [21]Marín-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M: Microglia promote the death of developing Purkinje cells. Neuron 2004, 41:535-547.
• [22]Mallat M, Marín-Teva JL, Chéret C: Phagocytosis in the developing CNS: more than clearing the corpses. Curr Opin Neurobiol 2005, 15:101-107.
• [23]Sessa G, Podini P, Mariani M, Meroni A, Spreafico R, Sinigaglia F, Colonna M, Panina P, Meldolesi J: Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia. Eur J Neurosci 2004, 20:2617-2628.
• [24]Laflamme N, Rivest S: Toll-like receptor 4: the missing link of the cerebral innate immune response triggered by circulating gram-negative bacterial cell wall components. FASEB J 2001, 15:155-163.
• [25]Kanzler H, Barrat FJ, Hessel EM, Coffman RL: Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat Med 2007, 13:552-559.
• [26]Lehnardt S, Schott E, Trimbuch T, Laubisch D, Krueger C, Wulczyn G, Nitsch R, Weber JR: A vicious cycle involving release of heat shock protein 60 from injured cells and activation of toll-like receptor 4 mediates neurodegeneration in the CNS. J Neurosci 2008, 28:2320-2331.
• [27]Stefano L, Racchetti G, Bianco F, Passini N, Gupta RS, PaninaBordignon P, Meldolesi J: The surface-exposed chaperone, Hsp60, is an agonist of the microglial TREM2 receptor. J Neurochem 2009, 110:284-294.
• [28]Hamerman JA, Tchao NK, Lowell CA, Lanier LL: Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nat Immunol 2005, 6:579-586.
• [29]Hamerman JA, Jarjoura JR, Humphrey MB, Nakamura MC, Seaman WE, Lanier LL: Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J Immunol 2006, 177:2051-2055.