Macrophage antigen complex-1 mediates reactive microgliosis and progressive dopaminergic neurodegeneration in the MPTP model of Parkinson's disease

Xiaoming Hu, Dan Zhang, Hao Pang, W. Michael Caudle, Yachen Li, Huiming Gao, Yuxin Liu, Li Qian, Belinda Wilson, Donato A. Di Monte, Syed F. Ali, Jing Zhang, Michelle Block, Jau Shyong Hong

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Abstract

Neuronal death is known to trigger reactive microgliosis. However, little is known regarding the manner by which microglia are activated by injured neurons and how microgliosis participates in neurodegeneration. In this study we delineate the critical role of macrophage Ag complex-1 (MAC1), a member of the β2 integrin family, in mediating reactive microgliosis and promoting dopaminergic (DAergic) neurodegeneration in the 1-methyl-4-phenyl-1,2, 3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. MAC1 deficiency greatly attenuated the DAergic neurodegeneration induced by MPTP or 1-methyl-4-phenyl-pyridium iodide (MPP+) exposure both in vivo and in vitro, respectively. Reconstituted experiments created by adding microglia from MAC1-/- or MAC1+/+ mice back to MAC1+/+ neuron-enriched cultures showed that microglia with functional MAC1 expression was mandatory for microglia-enhanced neurotoxicity. Both in vivo and in vitro morphological and Western blot studies demonstrated that MPTP/MPP+ produced less microglia activation in MAC1-/- mice than MAC1 +/+ mice. Further mechanistic studies revealed that a MPP +-mediated increase in superoxide production was reduced in MAC1 -/- neuron-glia cultures compared with MAC1+/+ cultures. The stunted production of superoxide in MAC1-/- microglia is likely linked to the lack of translocation of the cytosolic NADPH oxidase (PHOX) subunit (p47phox) to the membrane. In addition, the production of PGE2 markedly decreased in neuron plus MAC1-/- microglia cocultures vs neuron plus MAC1+/+ microglia cocultures. Taken together, these results demonstrate that MAC1 plays a critical role in MPTP/MPP+-induced reactive microgliosis and further support the hypothesis that reactive microgliosis is an essential step in the self-perpetuating cycle leading to progressive DAergic neurodegeneration observed in Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)7194-7204
Number of pages11
JournalJournal of Immunology
Volume181
Issue number10
StatePublished - Nov 15 2008
Externally publishedYes

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Macrophage-1 Antigen
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Parkinson Disease
Macrophages
Microglia
Neurons
Coculture Techniques
Superoxides
Phenazopyridine
Macrophage Activation
NADPH Oxidase
Iodides
Dinoprostone
Integrins
Neuroglia

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Macrophage antigen complex-1 mediates reactive microgliosis and progressive dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. / Hu, Xiaoming; Zhang, Dan; Pang, Hao; Caudle, W. Michael; Li, Yachen; Gao, Huiming; Liu, Yuxin; Qian, Li; Wilson, Belinda; Di Monte, Donato A.; Ali, Syed F.; Zhang, Jing; Block, Michelle; Hong, Jau Shyong.

In: Journal of Immunology, Vol. 181, No. 10, 15.11.2008, p. 7194-7204.

Research output: Contribution to journalArticle

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, M & Hong, JS 2008, 'Macrophage antigen complex-1 mediates reactive microgliosis and progressive dopaminergic neurodegeneration in the MPTP model of Parkinson's disease', Journal of Immunology, vol. 181, no. 10, pp. 7194-7204.
Hu, Xiaoming ; Zhang, Dan ; Pang, Hao ; Caudle, W. Michael ; Li, Yachen ; Gao, Huiming ; Liu, Yuxin ; Qian, Li ; Wilson, Belinda ; Di Monte, Donato A. ; Ali, Syed F. ; Zhang, Jing ; Block, Michelle ; Hong, Jau Shyong. / Macrophage antigen complex-1 mediates reactive microgliosis and progressive dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. In: Journal of Immunology. 2008 ; Vol. 181, No. 10. pp. 7194-7204.
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abstract = "Neuronal death is known to trigger reactive microgliosis. However, little is known regarding the manner by which microglia are activated by injured neurons and how microgliosis participates in neurodegeneration. In this study we delineate the critical role of macrophage Ag complex-1 (MAC1), a member of the β2 integrin family, in mediating reactive microgliosis and promoting dopaminergic (DAergic) neurodegeneration in the 1-methyl-4-phenyl-1,2, 3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. MAC1 deficiency greatly attenuated the DAergic neurodegeneration induced by MPTP or 1-methyl-4-phenyl-pyridium iodide (MPP+) exposure both in vivo and in vitro, respectively. Reconstituted experiments created by adding microglia from MAC1-/- or MAC1+/+ mice back to MAC1+/+ neuron-enriched cultures showed that microglia with functional MAC1 expression was mandatory for microglia-enhanced neurotoxicity. Both in vivo and in vitro morphological and Western blot studies demonstrated that MPTP/MPP+ produced less microglia activation in MAC1-/- mice than MAC1 +/+ mice. Further mechanistic studies revealed that a MPP +-mediated increase in superoxide production was reduced in MAC1 -/- neuron-glia cultures compared with MAC1+/+ cultures. The stunted production of superoxide in MAC1-/- microglia is likely linked to the lack of translocation of the cytosolic NADPH oxidase (PHOX) subunit (p47phox) to the membrane. In addition, the production of PGE2 markedly decreased in neuron plus MAC1-/- microglia cocultures vs neuron plus MAC1+/+ microglia cocultures. Taken together, these results demonstrate that MAC1 plays a critical role in MPTP/MPP+-induced reactive microgliosis and further support the hypothesis that reactive microgliosis is an essential step in the self-perpetuating cycle leading to progressive DAergic neurodegeneration observed in Parkinson's disease.",
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AU - Li, Yachen

AU - Gao, Huiming

AU - Liu, Yuxin

AU - Qian, Li

AU - Wilson, Belinda

AU - Di Monte, Donato A.

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AU - Zhang, Jing

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AU - Hong, Jau Shyong

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N2 - Neuronal death is known to trigger reactive microgliosis. However, little is known regarding the manner by which microglia are activated by injured neurons and how microgliosis participates in neurodegeneration. In this study we delineate the critical role of macrophage Ag complex-1 (MAC1), a member of the β2 integrin family, in mediating reactive microgliosis and promoting dopaminergic (DAergic) neurodegeneration in the 1-methyl-4-phenyl-1,2, 3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. MAC1 deficiency greatly attenuated the DAergic neurodegeneration induced by MPTP or 1-methyl-4-phenyl-pyridium iodide (MPP+) exposure both in vivo and in vitro, respectively. Reconstituted experiments created by adding microglia from MAC1-/- or MAC1+/+ mice back to MAC1+/+ neuron-enriched cultures showed that microglia with functional MAC1 expression was mandatory for microglia-enhanced neurotoxicity. Both in vivo and in vitro morphological and Western blot studies demonstrated that MPTP/MPP+ produced less microglia activation in MAC1-/- mice than MAC1 +/+ mice. Further mechanistic studies revealed that a MPP +-mediated increase in superoxide production was reduced in MAC1 -/- neuron-glia cultures compared with MAC1+/+ cultures. The stunted production of superoxide in MAC1-/- microglia is likely linked to the lack of translocation of the cytosolic NADPH oxidase (PHOX) subunit (p47phox) to the membrane. In addition, the production of PGE2 markedly decreased in neuron plus MAC1-/- microglia cocultures vs neuron plus MAC1+/+ microglia cocultures. Taken together, these results demonstrate that MAC1 plays a critical role in MPTP/MPP+-induced reactive microgliosis and further support the hypothesis that reactive microgliosis is an essential step in the self-perpetuating cycle leading to progressive DAergic neurodegeneration observed in Parkinson's disease.

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