Immunoregulation of microglial polarization: an unrecognized physiological function of α-synuclein

Li, Na; Stewart, Tessandra; Sheng, Lifu; Shi, Min; Cilento, Eugene M.; Wu, Yufeng; Hong, Jau Shyong; Zhang, Jing

doi:10.1186/s12974-020-01940-z

Cited by 29 publications

(14 citation statements)

References 72 publications

(112 reference statements)

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“…In particular, treatment of microglial cells with non-aggregated aSyn was shown to increase phagocytosis and enhance pro-inflammatory cytokines release, NF-kB nuclear translocation and microglial migration [ 439 , 468 , 473 , 474 , 475 ], whereas addition of fibrillar aSyn in BV2 cells was reported to reduce their phagocytic activity [ 474 ]. In agreement, incubation of human microglial cell lines or primary microglial cells with monomeric aSyn triggered the release of various pro-inflammatory factors [ 476 , 477 , 478 , 479 ]; however, recently, it has been suggested that monomeric, contrarily to oligomeric aSyn, promotes an anti-inflammatory phenotype of microglia [ 480 ]. Other groups have found that aggregated aSyn leads to increased TNFa and ROS production, both related to cell toxicity [ 456 , 481 , 482 , 483 ].…”

Section: Glia In the Cns: Scavengers Of Extracellular Asynmentioning

confidence: 87%

Neurons and Glia Interplay in α-Synucleinopathies

Mavroeidi

Xilouri

2021

IJMS

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Accumulation of the neuronal presynaptic protein alpha-synuclein within proteinaceous inclusions represents the key histophathological hallmark of a spectrum of neurodegenerative disorders, referred to by the umbrella term a-synucleinopathies. Even though alpha-synuclein is expressed predominantly in neurons, pathological aggregates of the protein are also found in the glial cells of the brain. In Parkinson’s disease and dementia with Lewy bodies, alpha-synuclein accumulates mainly in neurons forming the Lewy bodies and Lewy neurites, whereas in multiple system atrophy, the protein aggregates mostly in the glial cytoplasmic inclusions within oligodendrocytes. In addition, astrogliosis and microgliosis are found in the synucleinopathy brains, whereas both astrocytes and microglia internalize alpha-synuclein and contribute to the spread of pathology. The mechanisms underlying the pathological accumulation of alpha-synuclein in glial cells that under physiological conditions express low to non-detectable levels of the protein are an area of intense research. Undoubtedly, the presence of aggregated alpha-synuclein can disrupt glial function in general and can contribute to neurodegeneration through numerous pathways. Herein, we summarize the current knowledge on the role of alpha-synuclein in both neurons and glia, highlighting the contribution of the neuron-glia connectome in the disease initiation and progression, which may represent potential therapeutic target for a-synucleinopathies.

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Section: Glia In the Cns: Scavengers Of Extracellular Asynmentioning

confidence: 87%

Neurons and Glia Interplay in α-Synucleinopathies

Mavroeidi

Xilouri

2021

IJMS

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“…LPS-induced M1 polarization has been broadly validated in rodents, but doses of LPS vary between studies [10,[12][13][14]25] . Yang injected mice i.p.…”

Section: Discussionmentioning

confidence: 99%

Different doses of systemic LPS induce different degrees of polarization of microglia and astrocytes

Afang¹,

Su²,

Liu³

et al. 2021

Preprint

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Background Microglia and astrocytes are activated in different phenotypes to exert opposite effects. The recently reported intraperitoneal injection of 5 mg/kg lipopolysaccharides (LPS) to promote A1 astrocytes by activating M1 microglia was found to cause high mortality. Furthermore, reported doses of systemic LPS used to induce M1 microglia vary widely (0.1 ~ 5 mg/kg). We aimed to study microglia and astrocytes polarization induced by various LPS doses in the central nervous system, and assess whether downregulation of C3a receptor (C3aR) in astrocytes contributes to an increased A2/A1 ratio. Methods Rats were randomly divided into six LPS dosage groups (0, 0.1, 0.33, 1, 3, and 5 mg/kg, intraperitoneally). Seventy-two genes for A1, A2, A-pan, M1, and M2 markers were detected by real-time polymerase chain reaction 24 hours after LPS treatment in the cerebral cortex, hippocampus, and spinal cord. C3aR in astrocytes was knocked down by intrathecal injection of AAV-C3aR-GFAP 21 days before LPS administration. Co-immunofluorescence of C3aR with microglia, astrocytes, and neuron markers were performed to verify the specificity of C3aR knockdown in astrocytes. Changes in the 72 genes in the spinal cord were detected again 24 hours after LPS injection. Results Systemic LPS activated not only A1 and M1, but also A2, M2, and A-pan in the cerebral cortex, hippocampus, and spinal cord. The same LPS dose induced a similar activation level of M1 and M2, both of which were upregulated with increasing LPS. A1 and A-pan were polarized more than A2 at all LPS doses in the cortex and spinal cord. Microglia were more activated at 5 mg/kg than at 3 mg/kg LPS, but astrocytes presented no activation advantage at 5 mg/kg LPS. Marco, Ym1, and C3 showed a significant dose-dependent increase in LPS concentration. Specific knockdown of C3aR in astrocytes upregulated more markers of A2 than A1 and A-pan. Conclusions A larger systemic LPS dose contributes to greater polarization of M1 and M2 microglia, but no dominant phenotype. More A1 and A-pan astrocytes were activated than A2, even at low LPS doses. Downregulation of C3aR in astrocytes contributes to the polarization of anti-inflammatory phenotypes induced by LPS.

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“…In particular, A53T mutant rapidly induces microgliosis through the recruitment of mitogen-activated protein kinase (MAPKs), NF-κB, activator protein 1 (AP-1) and subsequently the activation of nuclear factor erythroid 2–related factor 2 (Nrf2). In contrast, physiological monomeric α-synuclein boosts phagocytosis [ 91 ] and promotes anti-inflammatory microglial functions through decreasing extracellular signal–regulated kinase (ERK) activation and increasing peroxisome proliferator-activated receptor γ (PPARγ) pathway activity.…”

Section: The Contribution Of Microglia To Pdmentioning

confidence: 99%

The immunology of Parkinson’s disease

et al. 2022

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder which affects 6.1 million people worldwide. The neuropathological hallmarks include the loss of dopaminergic neurons in the substantia nigra, the presence of Lewy bodies and Lewy neurites caused by α-synuclein aggregation, and neuroinflammation in the brain. The prodromal phase happens years before the onset of PD during which time many patients show gastro-intestinal symptoms. These symptoms are in support of Braak’s theory and model where pathological α‐synuclein propagates from the gut to the brain. Importantly, immune responses play a determinant role in the pathogenesis of Parkinson’s disease. The innate immune responses triggered by microglia can cause neuronal death and disease progression. In addition, T cells infiltrate into the brains of PD patients and become involved in the adaptive immune responses. Interestingly, α‐synuclein is associated with both innate and adaptive immune responses by directly interacting with microglia and T cells. Here, we give a detailed review of the immunobiology of Parkinson’s disease, focusing on the role α-synuclein in the gut-brain axis hypothesis, the innate and adaptive immune responses involved in the disease, and current treatments.

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Immunoregulation of microglial polarization: an unrecognized physiological function of α-synuclein

Cited by 29 publications

References 72 publications

Neurons and Glia Interplay in α-Synucleinopathies

Neurons and Glia Interplay in α-Synucleinopathies

Different doses of systemic LPS induce different degrees of polarization of microglia and astrocytes

The immunology of Parkinson’s disease

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