Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains

Imamura, Kazuhiro; Hishikawa, Nozomi; Sawada, Makoto; Nagatsu, Toshiharu; Yoshida, Mari; Hashizume, Yoshio

doi:10.1007/s00401-003-0766-2

Cited by 662 publications

(503 citation statements)

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“…Statistical parametric mapping allows exploratory voxel by voxel group comparison throughout the entire brain volume without requiring a priori hypothesis. The authors in essence confirmed in vivo what is known from neuropathologic studies; 49 namely, that there is widespread microglial activation in the substantia nigra and basal ganglia, but also in cortical association regions (i.e., hippocampus, transentorhinal cortex, cingulated cortex), the same regions that have a high burden of Lewy body pathology in the early stages of the disease. 50 It is important to note that PD is emerging as a multisystem disease with involvement of regions outside the nigrostriatal connections and that a widely distributed tissue pathology is already present in the early clinical phase of the disease.…”

Section: Movement Disorderssupporting

confidence: 64%

Positron Emission Tomography Imaging of Neuroinflammation

et al. 2007

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In the diseased brain, upon activation microglia express binding sites for synthetic ligands designed to recognize the 18-kDa translocator protein TP-18, which is part of the so-called peripheral benzodiazepine receptor complex. PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide], the prototype synthetic ligand, has been widely used for the functional characterization of TP-18. Its cellular source in activated microglia has been established using high-resolution, single-cell autoradiography with the R-enantiomer [3H](R)-PK11195. Radiolabeled [11C](R)-PK11195 has been used to image active brain disease with positron emission tomography. Consistent with experimental and postmortem observations of a characteristically distributed pattern of microglia activation in areas of focal pathology, as well as in anterograde and retrograde projection areas, the in vivo regional [11C](R)-PK11195 signal is found in active focal lesions and over time also along the affected neural tracts and their respective cortical and subcortical projection areas. Thus, a profile of active disease emerges that matches some of the typical distribution patterns known from structural neuroimaging techniques, but additionally shows involvement of brain regions linked through neural pathways. In the context of cell-based in vivo neuropathology, the image data are thus best interpreted in the context of the emerging cellular understanding of brain disease or damage, rather than the definitions of clinical diagnosis. One important observation, borne out by experiment, is the long latency with which activated microglia or increased PK11195 retention appear to gradually emerge and remain in distal areas secondarily affected by disease, supporting speculations that the presence of activated microglia is an important corollary of brain plasticity

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Section: Movement Disorderssupporting

confidence: 64%

Positron Emission Tomography Imaging of Neuroinflammation

et al. 2007

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“…Thus in PD itself, α‐synuclein itself might be an antigen used by MHC II during antigen presentation and thus leading to the observed glial infiltration in PD (Hunot and Hirsch, 2003). However it has been also demonstrated that MHC II is upregulated in Parkinson brains, and was not linked to the presence of Lewy‐bodies, indicating, that α‐synuclein might only play a minor role in the recruitment of MHC II positive microglia, and invasion occurs due to the neuronal injury and the associated phagocytosis (Imamura et al, 2003; McGeer et al, 1988). …”

Section: Discussionmentioning

confidence: 99%

“…Under normal conditions the central nervous system expresses low levels of MHC II (Shrikant and Benveniste, 1996); however increases in MHC II levels have been documented in a number of pathological states including multiple sclerosis (Hofman et al, 1986) and Alzheimer's disease (Parachikova et al, 2007). Increases in MHC II‐positive cells have long been recognised in human post‐mortem tissue from PD patients (Imamura et al, 2003; McGeer et al, 1988). Also an increase in the number of MHC II‐positive microglia is seen in mice treated with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), a drug which induces a PD‐like disease in mice (Kurkowska‐Jastrzebska et al, 1999a, 1999b).…”

Section: Introductionmentioning

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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“…1,2 Overwhelmingly activated microglia are present in the vicinity of the degenerating neurons in the substantia nigra (SN) of PD patients. 3 Microglial activation can be classified into two major phenotypes defined as 'classical activation' (also termed M1 phenotype or overactivated phenotype) and 'alternative activation' (M2 phenotype). 4,5 M1 microglia polarization is associated with the production and release of multiple proinflammatory cytokines.…”

mentioning

confidence: 99%

Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease

et al. 2013

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Classical activation (M1 phenotype) and alternative activation (M2 phenotype) are the two polars of microglial activation states that can produce either detrimental or beneficial effects in the central nervous system (CNS). Harnessing the beneficial properties of microglia cells by modulating their polarization states provides great potential for the treatment of Parkinson's disease (PD). However, the epigenetic mechanism that regulates microglia polarization remains elusive. Here, we reported that histone H3K27me3 demethylase Jumonji domain containing 3 (Jmjd3) was essential for M2 microglia polarization. Suppression of Jmjd3 in N9 microglia inhibited M2 polarization and simultaneously exaggerated M1 microglial inflammatory responses, which led to extensive neuron death in vitro. We also observed that the suppression of Jmjd3 in the substantia nigra (SN) in vivo dramatically caused microglial overactivation and exacerbated dopamine (DA) neuron death in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-intoxicated mouse model of PD. Moreover, we showed that the Jmjd3 level was lower in the midbrain of aged mice, which was accompanied by an elevated level of H3K27me3 and an increased ratio of M1 to M2 markers, suggesting that aging is an important factor in switching the microglia phenotypes. Overall, our studies indicate that Jmjd3 is able to enhance the polarization of M2 microglia by modifying histone H3K27me3, and therefore it has a pivotal role in the switch of microglia phenotypes that may contribute to the immune pathogenesis of PD.

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Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains

Cited by 662 publications

References 50 publications

Positron Emission Tomography Imaging of Neuroinflammation

Positron Emission Tomography Imaging of Neuroinflammation

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

Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease

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