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PD-L1 signaling in reactive astrocytes counteracts neuroinflammation and ameliorates neuronal damage after traumatic brain injury
BACKGROUND: Tissue damage and cellular destruction are the major events in traumatic brain injury (TBI), which trigger sterile neuroimmune and neuroinflammatory responses in the brain. While appropriate acute and transient neuroimmune and neuroinflammatory responses facilitate the repair and adaptat...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8822654/ https://www.ncbi.nlm.nih.gov/pubmed/35135580 http://dx.doi.org/10.1186/s12974-022-02398-x |
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author | Gao, Xiang Li, Wei Syed, Fahim Yuan, Fang Li, Ping Yu, Qigui |
author_facet | Gao, Xiang Li, Wei Syed, Fahim Yuan, Fang Li, Ping Yu, Qigui |
author_sort | Gao, Xiang |
collection | PubMed |
description | BACKGROUND: Tissue damage and cellular destruction are the major events in traumatic brain injury (TBI), which trigger sterile neuroimmune and neuroinflammatory responses in the brain. While appropriate acute and transient neuroimmune and neuroinflammatory responses facilitate the repair and adaptation of injured brain tissues, prolonged and excessive neuroimmune and neuroinflammatory responses exacerbate brain damage. The mechanisms that control the intensity and duration of neuroimmune and neuroinflammatory responses in TBI largely remain elusive. METHODS: We used the controlled cortical impact (CCI) model of TBI to study the role of immune checkpoints (ICPs), key regulators of immune homeostasis, in the regulation of neuroimmune and neuroinflammatory responses in the brain in vivo. RESULTS: We found that de novo expression of PD-L1, a potent inhibitory ICP, was robustly and transiently induced in reactive astrocytes, but not in microglia, neurons, or oligodendrocyte progenitor cells (OPCs). These PD-L1(+) reactive astrocytes were highly enriched to form a dense zone around the TBI lesion. Blockade of PD-L1 signaling enlarged brain tissue cavity size, increased infiltration of inflammatory Ly-6C(High) monocytes/macrophages (M/Mɸ) but not tissue-repairing Ly-6C(Low)F4/80(+) M/Mɸ, and worsened TBI outcomes in mice. PD-L1 gene knockout enhanced production of CCL2 that is best known for its ability to interact with its cognate receptor CCR2 on Ly-6C(High) M/Mϕ to chemotactically recruit these cells into inflammatory sites. Mechanically, PD-L1 signaling in astrocytes likely exhibits dual inhibitory activities for the prevention of excessive neuroimmune and neuroinflammatory responses to TBI through (1) the PD-1/PD-L1 axis to suppress the activity of brain-infiltrating PD-1(+) immune cells, such as PD-1(+) T cells, and (2) PD-L1 intrinsic signaling to regulate the timing and intensity of astrocyte reactions to TBI. CONCLUSIONS: PD-L1(+) astrocytes act as a gatekeeper to the brain to control TBI-related neuroimmune and neuroinflammatory responses, thereby opening a novel avenue to study the role of ICP–neuroimmune axes in the pathophysiology of TBI and other neurological disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02398-x. |
format | Online Article Text |
id | pubmed-8822654 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-88226542022-02-08 PD-L1 signaling in reactive astrocytes counteracts neuroinflammation and ameliorates neuronal damage after traumatic brain injury Gao, Xiang Li, Wei Syed, Fahim Yuan, Fang Li, Ping Yu, Qigui J Neuroinflammation Research BACKGROUND: Tissue damage and cellular destruction are the major events in traumatic brain injury (TBI), which trigger sterile neuroimmune and neuroinflammatory responses in the brain. While appropriate acute and transient neuroimmune and neuroinflammatory responses facilitate the repair and adaptation of injured brain tissues, prolonged and excessive neuroimmune and neuroinflammatory responses exacerbate brain damage. The mechanisms that control the intensity and duration of neuroimmune and neuroinflammatory responses in TBI largely remain elusive. METHODS: We used the controlled cortical impact (CCI) model of TBI to study the role of immune checkpoints (ICPs), key regulators of immune homeostasis, in the regulation of neuroimmune and neuroinflammatory responses in the brain in vivo. RESULTS: We found that de novo expression of PD-L1, a potent inhibitory ICP, was robustly and transiently induced in reactive astrocytes, but not in microglia, neurons, or oligodendrocyte progenitor cells (OPCs). These PD-L1(+) reactive astrocytes were highly enriched to form a dense zone around the TBI lesion. Blockade of PD-L1 signaling enlarged brain tissue cavity size, increased infiltration of inflammatory Ly-6C(High) monocytes/macrophages (M/Mɸ) but not tissue-repairing Ly-6C(Low)F4/80(+) M/Mɸ, and worsened TBI outcomes in mice. PD-L1 gene knockout enhanced production of CCL2 that is best known for its ability to interact with its cognate receptor CCR2 on Ly-6C(High) M/Mϕ to chemotactically recruit these cells into inflammatory sites. Mechanically, PD-L1 signaling in astrocytes likely exhibits dual inhibitory activities for the prevention of excessive neuroimmune and neuroinflammatory responses to TBI through (1) the PD-1/PD-L1 axis to suppress the activity of brain-infiltrating PD-1(+) immune cells, such as PD-1(+) T cells, and (2) PD-L1 intrinsic signaling to regulate the timing and intensity of astrocyte reactions to TBI. CONCLUSIONS: PD-L1(+) astrocytes act as a gatekeeper to the brain to control TBI-related neuroimmune and neuroinflammatory responses, thereby opening a novel avenue to study the role of ICP–neuroimmune axes in the pathophysiology of TBI and other neurological disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02398-x. BioMed Central 2022-02-08 /pmc/articles/PMC8822654/ /pubmed/35135580 http://dx.doi.org/10.1186/s12974-022-02398-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Gao, Xiang Li, Wei Syed, Fahim Yuan, Fang Li, Ping Yu, Qigui PD-L1 signaling in reactive astrocytes counteracts neuroinflammation and ameliorates neuronal damage after traumatic brain injury |
title | PD-L1 signaling in reactive astrocytes counteracts neuroinflammation and ameliorates neuronal damage after traumatic brain injury |
title_full | PD-L1 signaling in reactive astrocytes counteracts neuroinflammation and ameliorates neuronal damage after traumatic brain injury |
title_fullStr | PD-L1 signaling in reactive astrocytes counteracts neuroinflammation and ameliorates neuronal damage after traumatic brain injury |
title_full_unstemmed | PD-L1 signaling in reactive astrocytes counteracts neuroinflammation and ameliorates neuronal damage after traumatic brain injury |
title_short | PD-L1 signaling in reactive astrocytes counteracts neuroinflammation and ameliorates neuronal damage after traumatic brain injury |
title_sort | pd-l1 signaling in reactive astrocytes counteracts neuroinflammation and ameliorates neuronal damage after traumatic brain injury |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8822654/ https://www.ncbi.nlm.nih.gov/pubmed/35135580 http://dx.doi.org/10.1186/s12974-022-02398-x |
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