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NG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis
BACKGROUND: Brain innate immunity is vital for maintaining normal brain functions. Immune homeostatic imbalances play pivotal roles in the pathogenesis of neurological diseases including Parkinson’s disease (PD). However, the molecular and cellular mechanisms underlying the regulation of brain innat...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857135/ https://www.ncbi.nlm.nih.gov/pubmed/31727112 http://dx.doi.org/10.1186/s12916-019-1439-x |
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author | Zhang, Shu-zhen Wang, Qin-qin Yang, Qiao-qiao Gu, Huan-yu Yin, Yan-qing Li, Yan-dong Hou, Jin-can Chen, Rong Sun, Qing-qing Sun, Ying-feng Hu, Gang Zhou, Jia-wei |
author_facet | Zhang, Shu-zhen Wang, Qin-qin Yang, Qiao-qiao Gu, Huan-yu Yin, Yan-qing Li, Yan-dong Hou, Jin-can Chen, Rong Sun, Qing-qing Sun, Ying-feng Hu, Gang Zhou, Jia-wei |
author_sort | Zhang, Shu-zhen |
collection | PubMed |
description | BACKGROUND: Brain innate immunity is vital for maintaining normal brain functions. Immune homeostatic imbalances play pivotal roles in the pathogenesis of neurological diseases including Parkinson’s disease (PD). However, the molecular and cellular mechanisms underlying the regulation of brain innate immunity and their significance in PD pathogenesis are still largely unknown. METHODS: Cre-inducible diphtheria toxin receptor (iDTR) and diphtheria toxin-mediated cell ablation was performed to investigate the impact of neuron-glial antigen 2 (NG2) glia on the brain innate immunity. RNA sequencing analysis was carried out to identify differentially expressed genes in mouse brain with ablated NG2 glia and lipopolysaccharide (LPS) challenge. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice were used to evaluate neuroinflammatory response in the presence or absence of NG2 glia. The survival of dopaminergic neurons or glial cell activation was evaluated by immunohistochemistry. Co-cultures of NG2 glia and microglia were used to examine the influence of NG2 glia to microglial activation. RESULTS: We show that NG2 glia are required for the maintenance of immune homeostasis in the brain via transforming growth factor-β2 (TGF-β2)-TGF-β type II receptor (TGFBR2)-CX3C chemokine receptor 1 (CX3CR1) signaling, which suppresses the activation of microglia. We demonstrate that mice with ablated NG2 glia display a profound downregulation of the expression of microglia-specific signature genes and remarkable inflammatory response in the brain following exposure to endotoxin lipopolysaccharides. Gain- or loss-of-function studies show that NG2 glia-derived TGF-β2 and its receptor TGFBR2 in microglia are key regulators of the CX3CR1-modulated immune response. Furthermore, deficiency of NG2 glia contributes to neuroinflammation and nigral dopaminergic neuron loss in MPTP-induced mouse PD model. CONCLUSIONS: These findings suggest that NG2 glia play a critical role in modulation of neuroinflammation and provide a compelling rationale for the development of new therapeutics for neurological disorders. |
format | Online Article Text |
id | pubmed-6857135 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-68571352019-12-05 NG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis Zhang, Shu-zhen Wang, Qin-qin Yang, Qiao-qiao Gu, Huan-yu Yin, Yan-qing Li, Yan-dong Hou, Jin-can Chen, Rong Sun, Qing-qing Sun, Ying-feng Hu, Gang Zhou, Jia-wei BMC Med Research Article BACKGROUND: Brain innate immunity is vital for maintaining normal brain functions. Immune homeostatic imbalances play pivotal roles in the pathogenesis of neurological diseases including Parkinson’s disease (PD). However, the molecular and cellular mechanisms underlying the regulation of brain innate immunity and their significance in PD pathogenesis are still largely unknown. METHODS: Cre-inducible diphtheria toxin receptor (iDTR) and diphtheria toxin-mediated cell ablation was performed to investigate the impact of neuron-glial antigen 2 (NG2) glia on the brain innate immunity. RNA sequencing analysis was carried out to identify differentially expressed genes in mouse brain with ablated NG2 glia and lipopolysaccharide (LPS) challenge. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice were used to evaluate neuroinflammatory response in the presence or absence of NG2 glia. The survival of dopaminergic neurons or glial cell activation was evaluated by immunohistochemistry. Co-cultures of NG2 glia and microglia were used to examine the influence of NG2 glia to microglial activation. RESULTS: We show that NG2 glia are required for the maintenance of immune homeostasis in the brain via transforming growth factor-β2 (TGF-β2)-TGF-β type II receptor (TGFBR2)-CX3C chemokine receptor 1 (CX3CR1) signaling, which suppresses the activation of microglia. We demonstrate that mice with ablated NG2 glia display a profound downregulation of the expression of microglia-specific signature genes and remarkable inflammatory response in the brain following exposure to endotoxin lipopolysaccharides. Gain- or loss-of-function studies show that NG2 glia-derived TGF-β2 and its receptor TGFBR2 in microglia are key regulators of the CX3CR1-modulated immune response. Furthermore, deficiency of NG2 glia contributes to neuroinflammation and nigral dopaminergic neuron loss in MPTP-induced mouse PD model. CONCLUSIONS: These findings suggest that NG2 glia play a critical role in modulation of neuroinflammation and provide a compelling rationale for the development of new therapeutics for neurological disorders. BioMed Central 2019-11-15 /pmc/articles/PMC6857135/ /pubmed/31727112 http://dx.doi.org/10.1186/s12916-019-1439-x Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Zhang, Shu-zhen Wang, Qin-qin Yang, Qiao-qiao Gu, Huan-yu Yin, Yan-qing Li, Yan-dong Hou, Jin-can Chen, Rong Sun, Qing-qing Sun, Ying-feng Hu, Gang Zhou, Jia-wei NG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis |
title | NG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis |
title_full | NG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis |
title_fullStr | NG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis |
title_full_unstemmed | NG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis |
title_short | NG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis |
title_sort | ng2 glia regulate brain innate immunity via tgf-β2/tgfbr2 axis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857135/ https://www.ncbi.nlm.nih.gov/pubmed/31727112 http://dx.doi.org/10.1186/s12916-019-1439-x |
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