Microglia: a sensor for pathological events in the CNS

Kreutzberg, Georg W.

doi:10.1016/0166-2236(96)10049-7

Cited by 4,034 publications

(3,112 citation statements)

References 62 publications

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“…As microgliosis was not completely attenuated in MHC II null mice this suggests that some of the microgliosis seen following MPTP treatment is MHC II independent. Initial microglial activation is likely to be MHC II independent as this occurred before MHC II upregulation (Araneda et al, 1980) and following activation MHC II is upregulated (Kreutzberg, 1996). The reduction in microgliosis in MHC II null mice may be the result of a lack of infiltration/activation of CD4 + T‐cells and the release of IFNγ, indeed IFNγ levels were not upregulated by MPTP treatment in MHC II null mice as they were in wild‐type mice.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Martin

Santoro

Mustafa

et al. 2015

Glia

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Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post‐mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). In wild‐type mice MHC II levels in the ventral midbrain were upregulated 1–2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP‐induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon‐γ or tumour necrosis factor‐α in the brain after MPTP treatment, as was found in wild‐type mice. However, interleukin‐1β was significantly increased in both wild‐type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II‐mediated T cell activation is required for the full expression of pathology in this model of PD. GLIA 2016;64:386–395

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Section: Discussionmentioning

confidence: 99%

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Martin

Santoro

Mustafa

et al. 2015

Glia

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Section: Microgliamentioning

confidence: 99%

“…Activated microglia up-regulate a variety of surface receptors, including the major histocompatibility complex and complement receptors. They also undergo dramatic morphological changes from resting ramified cells to activated amoeboid microglia (Kreutzberg, 1996).Besides morphological changes and surface molecule upregulation, activated microglia secrete a host of soluble factors. A number of these factors, such as the glia-derived neurotrophic factor, are potentially beneficial to the survival of neurons, reminiscence of the neuroprotective role played by activated astrocytes, another major type of glial cells in the brain (Aloisi, 1999).…”

mentioning

confidence: 99%

Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism

Block

Hong

2005

Progress in Neurobiology

1,388

998

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“…Microglia and astrocyte are the major immune effector cells in the central nervous system (CNS) (Kreutzberg, 1996;Mentlein and Kendall, 2000). These cells respond quickly to even minor pathological changes by undergoing immunophenotypic alterations and by expressing signaling molecules, including inflammatory mediators (Ridet et al, 1997;Streit et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Many of these mediators can also act in a paracrine fashion, influencing the physiology of nearby neurons. Thus, the immune responses of activated glial cells are very complex phenomena, involving the interactions of several cell types with neurons and leading eventually to cell survival or injury via an inflammatory cascade (Kreutzberg, 1996;Matyszak, 1998). Although the immune system is designed to be protective, excessive or inappropriate activation of immune cells can lead to severe inflammatory diseases.…”

Section: Introductionmentioning

confidence: 99%

Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells

Lee

Park

Kim

et al. 2005

Glia

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PKR, the double-stranded RNA (dsRNA)-activated serine/threonine kinase, has been implicated as an important component of host responses to infection and various situations of cellular stress. The involvement of PKR in signal transduction and regulation of transcription suggested to us that it may play an important role in lipopolysaccharide (LPS)-induced activation of STAT1 in rat brain immune cells. We found that LPS rapidly stimulated the phosphorylation of PKR within 5 min, followed by phosphorylation of STAT1 at 2 h in rat primary microglia and astrocyte. Using 2-aminopurine (2-AP), a pharmacological inhibitor of PKR, and PKR-specific short interfering RNA (siRNA), we demonstrated that activation of PKR was essential for LPS-induced activation of STAT1. Inhibition of PKR activity by 2-AP resulted in suppression not only of STAT1 phosphorylation, but also of nuclear factors binding activity to GAS/ISRE elements. 2-AP also significantly suppressed the downstream events of LPS-stimulated STAT1 phosphorylation, including STAT-mediated transcriptional responses and generation of nitric oxide, a hallmark of brain inflammation. Consistent with these results, transfection of PKR-specific siRNA markedly attenuated all the STAT1 dependent inflammatory signaling responses tested. We further revealed that activation of PKR by LPS led to the induction of IFN-␤ through activation of NF-B, triggering the phosphorylation of STAT1 in rat brain glial cells. Taken together, these findings indicate that PKR functions as an essential modulator in LPS-induced STAT inflammatory signaling events, and provides new insight into endotoxin-induced CNS diseases following infection.

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Microglia: a sensor for pathological events in the CNS

Cited by 4,034 publications

References 62 publications

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism

Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells

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