Transforming growth factor-β1 acts via TβR-I on microglia to protect against MPP+-induced dopaminergic neuronal loss

Li, Zhan; Chen, Hui-Qiao; Huang, Yan; Qiu, Yihua; Peng, Yu‐Ping

doi:10.1016/j.bbi.2015.08.006

Cited by 43 publications

(31 citation statements)

References 61 publications

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“…The findings suggest that Treg cells do not depend on their cytokines to exert the direct neuroprotective effect. In fact, we have recently demonstrated that microglia are a required target for TGF-β1 neuroprotection against MPP + toxicity [19]. Thus, a cell-to-cell (Treg-to-neuron) communication with the aid of cell surface molecules becomes a key mechanism underlying Treg cell neuroprotection.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, the anti-inflammatory cytokine TGF-β1 does not directly act on dopaminergic neurons to protect them against the toxicity of 1-methyl-4-phenylpyridinium (MPP + ), a toxic cation that is concentrated in dopaminergic neurons via presynaptic dopamine transporters to kill the neurons, in our recent study [19]. We have demonstrated that microglia are required for mediation of TGF-β1 neuroprotection against MPP + toxicity [19]. Thus, the second communication way between Treg cells and dopaminergic neurons was investigated in the present study to better understand the rationality of Treg cell neuroprotection.…”

Section: Introductionmentioning

confidence: 99%

“…In the brain, the anti-inflammatory cytokines impair inflammatory milieu and glial activation but enhance the stabilization of the blood-brain barrier, and therefore they have neuroprotective properties [19, 20]. Nevertheless, the anti-inflammatory cytokine TGF-β1 does not directly act on dopaminergic neurons to protect them against the toxicity of 1-methyl-4-phenylpyridinium (MPP + ), a toxic cation that is concentrated in dopaminergic neurons via presynaptic dopamine transporters to kill the neurons, in our recent study [19]. We have demonstrated that microglia are required for mediation of TGF-β1 neuroprotection against MPP + toxicity [19].…”

Section: Introductionmentioning

confidence: 99%

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Treg Cells Protect Dopaminergic Neurons against MPP+ Neurotoxicity via CD47-SIRPA Interaction

Huang

Cao

et al. 2017

Cell Physiol Biochem

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Background/Aims: Regulatory T (Treg) cells have been associated with neuroprotection by inhibiting microglial activation in animal models of Parkinson's disease (PD), a progressive neurodegenerative disease characterized by dopaminergic neuronal loss in the nigrostriatal system. Herein, we show that Treg cells directly protect dopaminergic neurons against 1-methyl-4-phenylpyridinium (MPP⁺) neurotoxicity via an interaction between the two transmembrane proteins CD47 and signal regulatory protein α (SIRPA). Methods: Primary ventral mesencephalic (VM) cells or VM neurons were pretreated with Treg cells before MPP⁺ treatment. Transwell co-culture of Treg cells and VM neurons was used to assess the effects of the Treg cytokines transforming growth factor (TGF)-β1 and interleukin (IL)-10 on dopaminergic neurons. Live cell imaging system detected a dynamic contact of Treg cells with VM neurons that were stained with CD47 and SIRPA, respectively. Dopaminergic neuronal loss, which was assessed by the number of tyrosine hydroxylase (TH)-immunoreactive cells, was examined after silencing CD47 in Treg cells or silencing SIRPA in VM neurons. Results: Treg cells prevented MPP⁺-induced dopaminergic neuronal loss and glial inflammatory responses. TGF-β1 and IL-10 secreted from Treg cells did not significantly prevent MPP⁺-induced dopaminergic neuronal loss in transwell co-culture of Treg cells and VM neurons. CD47 and SIRPA were expressed by Treg cells and VM neurons, respectively. CD47-labeled Treg cells dynamically contacted with SIRPA-labeled VM neurons. Silencing CD47 gene in Treg cells impaired the ability of Treg cells to protect dopaminergic neurons against MPP⁺ toxicity. Similarly, SIRPA knockdown in VM neurons reduced the ability of Treg cell neuroprotection. Rac1/Akt signaling pathway in VM neurons was activated by CD47-SIRPA interaction between Treg cells and the neurons. Inhibiting Rac1/Akt signaling in VM neurons compromised Treg cell neuroprotection. Conclusion: Treg cells protect dopaminergic neurons against MPP⁺ neurotoxicity by a cell-to-cell contact mechanism underlying CD47-SIRPA interaction and Rac1/Akt activation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Treg Cells Protect Dopaminergic Neurons against MPP+ Neurotoxicity via CD47-SIRPA Interaction

Huang

Cao

et al. 2017

Cell Physiol Biochem

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“…Silencing of TGF-BR1 on microglia promoted neuroinflammation and neuronal damage in a model of Parkinson's disease (46). However, early astrocyte production of TGF-β1 appears to establish a permissive environment for autoimmunity and enhanced inflammation in EAE (49).…”

Section: +/Gfpmentioning

confidence: 99%

“…The importance of TGF-β1 on microglia development and homeostasis and the role of TGF-β1 and TGFBR1 after different neurological disease have recently been reported (8,(45)(46)(47). Tgfb1 and Tgfbr1 gene expression are highly upregulated in WT microglia during the second week after ICH.…”

Section: +/Gfpmentioning

confidence: 99%