Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Gao, Xiang, Li, Wei, Syed, Fahim, Yuan, Fang, Li, Ping, Yu, Qigui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
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
_version_ 1784646640431267840
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
work_keys_str_mv AT gaoxiang pdl1signalinginreactiveastrocytescounteractsneuroinflammationandamelioratesneuronaldamageaftertraumaticbraininjury
AT liwei pdl1signalinginreactiveastrocytescounteractsneuroinflammationandamelioratesneuronaldamageaftertraumaticbraininjury
AT syedfahim pdl1signalinginreactiveastrocytescounteractsneuroinflammationandamelioratesneuronaldamageaftertraumaticbraininjury
AT yuanfang pdl1signalinginreactiveastrocytescounteractsneuroinflammationandamelioratesneuronaldamageaftertraumaticbraininjury
AT liping pdl1signalinginreactiveastrocytescounteractsneuroinflammationandamelioratesneuronaldamageaftertraumaticbraininjury
AT yuqigui pdl1signalinginreactiveastrocytescounteractsneuroinflammationandamelioratesneuronaldamageaftertraumaticbraininjury