IL-17A exacerbates neuroinflammation and neurodegeneration by activating microglia in rodent models of Parkinson's disease

Li, Zhan; Qiu, Ao-Wang; Huang, Yan; Yang, Ya; Chen, Jinna; Gu, Tingting; Cao, Bangwei; Qiu, Yihua; Peng, Yu‐Ping

doi:10.1016/j.bbi.2019.07.026

Cited by 103 publications

(83 citation statements)

References 53 publications

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“…We therefore propose a dual role for IL-17 in physiological versus pathological conditions. Whereas, as shown here, the steady-state (and microbiotaindependent) production of IL-17 by meningeal γδ T cells promotes learning and memory, its exacerbated production (by γδ but also recruited CD4 + T cells) upon inflammation contributes to the pathogenesis of neuroinflammation and likely also to neurodegeneration, as recently suggested for Parkinson's disease (58,59).…”

Section: Discussionsupporting

confidence: 66%

Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

et al. 2019

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The notion of "immune privilege" of the brain has been revised to accommodate its infiltration, at steady state, by immune cells that participate in normal neurophysiology. However, the immune mechanisms that regulate learning and memory remain poorly understood. Here we show that noninflammatory IL-17 derived from a previously unknown foetal-derived meningeal-resident γδ T cell subset promotes cognition. When tested in classical spatial learning paradigms, mice lacking γδ T cells or IL-17 displayed deficient short-term memory, while retaining long-term memory.

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Section: Discussionsupporting

confidence: 66%

Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

et al. 2019

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“…and an increased number of Th17 cells in their peripheral blood [4][5][6][7][8]. Similar findings were found in mice intoxicated with MPTP [11][12][13][14]. The increased number of Th17 cells in the blood was correlated with augmented cell death of human induced pluripotent stem cell (hiPSC)-derived midbrain neurons from PD patients [10].…”

Section: An Increased Number Of T Lymphocytes Have Been Found In Postsupporting

confidence: 61%

“…Growing evidence has indicated that T helper cells might contribute to the cascade of neuroinflammation by breaking the balance of peripheral T helper 17 (Thl7) cells and regulatory T (Treg) cells [3][4][5][6][7][8][9]. IL-17-producing Th17 cells play a pivotal role in neuronal cell death, whereas Treg cells attenuate Th17 cells mediated nigrostriatal dopaminergic neuronal cell death [10][11][12]. As a result, imbalance between Th17 and Treg cells leads to neurodegeneration in the substantia nigra.…”

Section: Introductionmentioning

confidence: 99%

“…This might be due to the increased number of Th17 cells as well as the increased secretion of IL-17 in the serum of PD patients. Blockage of IL-17 or neutralizing it with an IL-17 antibody rescued neuronal death[6,7,[9][10][11]. Animal studies have revealed that an increased number of Th17 cells lead to tissue damage by producing a neurotoxic cytokine-interleukin IL-17[11][12][13][14]39], which is attenuated by Treg cells[12].…”

mentioning

confidence: 99%

“…Blockage of IL-17 or neutralizing it with an IL-17 antibody rescued neuronal death[6,7,[9][10][11]. Animal studies have revealed that an increased number of Th17 cells lead to tissue damage by producing a neurotoxic cytokine-interleukin IL-17[11][12][13][14]39], which is attenuated by Treg cells[12]. Animal studies and clinical trials have demonstrated that Ad-MSCs are a potential therapeutic strategy due to their capability of suppressing Th17 responses and inducing functional Treg cells[25][26][27][28][29][30][40][41][42].…”

mentioning

confidence: 99%

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Human adipose tissue-derived mesenchymal stem cells in Parkinson's disease：Inhibit T helper 17 cell differentiation and regulate immune balance towards a regulatory T cell phenotype

Lin

Liang

et al. 2020

Preprint

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Parkinson's disease (PD), known as a neurodegenerative disorder, shows typical pathology of neuroinflammation, which might be the result of the imbalance between regulatory T cells (Treg) and T helper 17 (Th17) cells. The present study aimed to investigate the modulating effect of Ad-MSCs on peripheral blood mononuclear cells (PBMCs) derived from PD patients. CD4 + peripheral blood T cells were isolated and co-cultured with Ad-MSCs at a ratio of 4:1 under Th17 or Treg polarizing conditions, respectively, for 4 days. Our results showed that Ad-MSCs specifically inhibited the differentiation of IL-17-producing CD4 + T cells collected from PBMCs of PD patients evidenced by the decreased expression of RORγt- the key transcription factor for Th17 cells, IL-6R, and IL-23R. In the meantime, Ad-MSCs and induced a functional CD4 + CD25 + Foxp3 + T regulatory cell phenotype evidenced by the secretion of IL-10. Furthermore, levels of LIF protein and its receptor mRNA were significantly increased under both polarizing conditions. These findings suggest that the regulation of the Th17/Treg balance by Ad-MSCs was correlated with the increase in LIF secretion. Therefore, Ad-MSCs are an important player in modulating inflammatory responses and a potential therapeutics for PD patients.

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CD4⁺ T cell‐associated cytokines induce a chronic pro‐inflammatory phenotype in induced pluripotent stem cell‐derived midbrain astrocytes

MacMahon Copas,

McComish,

Petrasca

et al. 2024

Glia

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Astrocytes are mediators of homeostasis but contribute to neuroinflammation in Parkinson's disease (PD). Mounting evidence suggests involvement of peripheral immune cells in PD pathogenesis. Therefore, this study aimed to determine the potential role of peripheral immune secreted cytokines in modulating midbrain astrocyte reactivity. Human iPSC‐derived midbrain astrocytes were exposed to 5% and 10% CD4+ T cell conditioned media (CD4CM) for 24 h, 72 h, and 7 days to assess chronic exposure. Additionally, astrocytes were exposed to the Th17 cell cytokine, IL‐17A (10 ng/mL), alone and in combination with TNF‐α (0.3 ng/mL) to assess potential synergistic effects of both cytokines at 24 h, 72 h, and 7 days. CD4CM induced acute and chronic alterations in midbrain astrocytes. Increased NFκB translocation to the nucleus, increased expression of the pro‐inflammatory genes, IL‐1β, CXCL10 at 24 h, C3, LCN2, IL‐6 at 24 and 48 h, as well as an increase in their release of pro‐inflammatory cytokines IL‐6 and CXCL10 at both these time points were observed. A synergistic response to the combination of IL‐17A and TNF‐α on increasing inflammatory gene expression and cytokine release occurred. IL‐17A and TNF‐α increased intensity of S100β at 24 h, decreased nuclear area and increased circularity of astrocytes at 72 h. A synergistic effect on γH2AX intensity at 72 h and an increase in LDH release at 7 days was observed. Our results demonstrate that IL‐17A and TNF‐α act synergistically, enhancing midbrain astrocyte reactivity to a similar degree as CD4CM. This highlights the importance of the peripheral immune secreted cytokines in increasing the reactivity status of midbrain astrocytes, implicating their role in PD.

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IL-17A exacerbates neuroinflammation and neurodegeneration by activating microglia in rodent models of Parkinson's disease

Cited by 103 publications

References 53 publications

Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

Human adipose tissue-derived mesenchymal stem cells in Parkinson's disease：Inhibit T helper 17 cell differentiation and regulate immune balance towards a regulatory T cell phenotype

CD4⁺ T cell‐associated cytokines induce a chronic pro‐inflammatory phenotype in induced pluripotent stem cell‐derived midbrain astrocytes

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IL-17A exacerbates neuroinflammation and neurodegeneration by activating microglia in rodent models of Parkinson's disease

Cited by 103 publications

References 53 publications

Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

Human adipose tissue-derived mesenchymal stem cells in Parkinson's disease：Inhibit T helper 17 cell differentiation and regulate immune balance towards a regulatory T cell phenotype

CD4+ T cell‐associated cytokines induce a chronic pro‐inflammatory phenotype in induced pluripotent stem cell‐derived midbrain astrocytes

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CD4⁺ T cell‐associated cytokines induce a chronic pro‐inflammatory phenotype in induced pluripotent stem cell‐derived midbrain astrocytes