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

Block, Michelle L.; Hong, Jau–Shyong

doi:10.1016/j.pneurobio.2005.06.004

Cited by 1,388 publications

(1,047 citation statements)

References 218 publications

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“…Microglia not only are phagocytes, clearing away cell debris (Egensperger et al 1996) but they are also the primary immunocompetent cells in the central nervous system (CNS) and may be involved in surveillance of tissue integrity and the protection of neuronal tissue during injury and disease (Streit et al 2005). On the other hand, microglia produce a multitude of factors which may be toxic to neurons thereby contributing to cell death in the CNS upon activation (Block and Hong 2005). In addition, glial cells may express most if not all of the activation and regulatory proteins of the complement system (Barnum 1995;Barnum 2002) and microglia up-regulate complement factor C1q in response to transient ischemia in the brain (Schafer et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Classical complement activation and acquired immune response pathways are not essential for retinal degeneration in the rd1 mouse

Rohrer

Demos

Frigg

et al. 2007

Experimental Eye Research

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Misregulation of the innate immune response and other immune-related processes have been suggested to play a critical role in the pathogenesis of a number of different neurodegenerative diseases, including age related macular degeneration. In an animal model for photoreceptor degeneration, several genes of the innate and acquired immune system were found to be differentially regulated in the retina during the degenerative process. In addition to this differential regulation of individual genes, we found that in the rd1 retina a significantly higher number of genes involved in immune-related responses were expressed at any given time during the degenerative period. The peak of immune-related gene expression was at postnatal day 14, coinciding with the peak of photoreceptor apoptosis in the rd1 mouse. We directly tested the potential involvement of acquired and innate immune responses in initiation and progression of photoreceptor degeneration by analyzing double mutant animals. Retinal morphology and photoreceptor apoptosis of rd1 mice on a SCID genetic background (no mature T-and B-cells) or in combination with a RAG-1 (no functional B-and T-cells) or a C1qα (no functional classical complement activation pathway) knockout was followed during the degenerative process using light microscopy or TUNEL staining, respectively. Although complement factor C1qα was highly up-regulated in the rd1 retina concomitantly with the degenerative process, lack of this protein did not protect the rd1 retina. Similarly, retinal degeneration and photoreceptor apoptosis appeared to proceed normally in the rd1 mouse lacking functional Band T-cells. Our results suggest that both, the classical complement system of innate immunity and a functional acquired immune response are not essential for the degenerative process in the rd1 mouse retina.

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Section: Discussionmentioning

confidence: 99%

Classical complement activation and acquired immune response pathways are not essential for retinal degeneration in the rd1 mouse

Rohrer

Demos

Frigg

et al. 2007

Experimental Eye Research

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“…Neuroinflammation characterized by the activation of glia has been closely associated with the pathogenesis of a number of neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), dementia resulting from infection with human immunodeficiency virus (HIV), and stroke [1] . Microglia, the resident macrophages in the normal healthy adult nervous system, form the first line of defense against injury to the central nervous system and are considered the major glia responsible for inflammation-mediated neurotoxicity.…”

Section: Introductionmentioning

confidence: 99%

“…Activation of microglia is often observed in neuronal injuries and is also induced after stimulation with lipopolysaccharide (LPS), interferon (IFN)-γ, and β-amyloid in vitro [2] . Upon activation, microglia can induce significant and highly detrimental neurotoxic effects attributable to excess production of a wide range of proinflammatory mediators, including inflammatory enzymes (eg, inducible nitric oxide synthase [iNOS] and cyclooxygenase-2 [COX-2]), pro-inflammatory cytokines (eg, interleukin-1β [IL-1β] and tumor necrosis factor-α [TNF-α]), chemokines (eg, monocyte chemoattractant protein [MCP-1]), and transcription factors (eg, nuclear factor-κB [NF-κB]) [1,2] . Accumulating evidence indicates that excessive activation of microglia results in a self-perpetuating cycle of neuronal death by releasing these neurotoxic mediators [1] .…”

Section: Introductionmentioning

confidence: 99%

Z-ligustilide attenuates lipopolysaccharide-induced proinflammatory response via inhibiting NF-κB pathway in primary rat microglia

Wang

et al. 2010

Acta Pharmacol Sin

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Aim: To investigate the anti-inflammatory effect of Z-ligustilide (LIG) on lipopolysaccharide (LPS)-activated primary rat microglia. Methods: Microglia were pretreated with LIG 1 h prior to stimulation with LPS (1 µg/mL). After 24 h, cell viability was tested with MTT, nitric oxide (NO) production was assayed with Griess reagent, and the content of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein (MCP-1) was measured with ELISA. Protein expression of the nuclear factor-κB (NF-κB) p65 subunit, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) was detected with immunocytochemistry 1 h or 24 h after LPS treatment. Results: LIG showed a concentration-dependent anti-inflammatory effect in LPS-activated microglia, without causing cytotoxicity. Pretreatment with LIG at 2.5, 5, 10, and 20 µmol/L decreased LPS-induced NO production to 75.9%, 54.4%, 43.1%, and 47.6% (P<0.05 or P<0.01), TNF-α content to 86.2%, 68.3%, 40.1%, and 39.9% (P<0.01, with the exception of 86.2% for 2.5 µmol/L LIG), IL-1β content to 31.5%, 27.7%, 0.6%, and 0% (P<0.01), and MCP-1 content to 84.4%, 50.3%, 45.1%, and 42.2% (P<0.05 or P<0.01), respectively, compared with LPS treatment alone. LIG (10 µmol/L) significantly inhibited LPS-stimulated immunoreactivity of activated NF-κB, COX-2, and iNOS (P<0.01 vs LPS group). Conclusion: LIG exerted a potent anti-inflammatory effect on microglia through inhibition of NF-κB pathway. The data provide direct evidence of the neuroprotective effects of LIG and the potential application of LIG for the treatment of the neuroinflammatory diseases characterized by excessive microglial activation.

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“…11,12 However, overactivated or dysregulated microglia are constantly involved in the pathogenesis of PD and serve to amplify neuronal damage caused by pathological stimuli and toxins, which in turn, induces more widespread damage to the neighboring neurons. 13,14 In contrast to the M1 phenotype, M2 microglia execute an anti-inflammatory effect and promote wound healing and tissue repair. 15,16 The major anti-inflammatory cytokines, such as interleukin-4 (IL-4), IL-13, IL-10 and transforming growth factor-b (TGF-b), initiate the alleviation of pro-inflammatory responses and enhance the expression of genes that are involved in tissue recovery and repair.…”

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

Cited by 1,388 publications

References 218 publications

Classical complement activation and acquired immune response pathways are not essential for retinal degeneration in the rd1 mouse

Classical complement activation and acquired immune response pathways are not essential for retinal degeneration in the rd1 mouse

Z-ligustilide attenuates lipopolysaccharide-induced proinflammatory response via inhibiting NF-κB pathway in primary rat microglia

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

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