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Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS). Infiltrating inflammatory immune cells perpetuate demyelination and axonal damage in the CNS and significantly contribute to pathology and clinical deficits. While the cytokine interferon (I...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568873/ https://www.ncbi.nlm.nih.gov/pubmed/37828609 http://dx.doi.org/10.1186/s12974-023-02917-4 |
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author | Smith, Brandon C. Tinkey, Rachel A. Brock, Orion D. Mariam, Arshiya Habean, Maria L. Dutta, Ranjan Williams, Jessica L. |
author_facet | Smith, Brandon C. Tinkey, Rachel A. Brock, Orion D. Mariam, Arshiya Habean, Maria L. Dutta, Ranjan Williams, Jessica L. |
author_sort | Smith, Brandon C. |
collection | PubMed |
description | Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS). Infiltrating inflammatory immune cells perpetuate demyelination and axonal damage in the CNS and significantly contribute to pathology and clinical deficits. While the cytokine interferon (IFN)γ is classically described as deleterious in acute CNS autoimmunity, we and others have shown astrocytic IFNγ signaling also has a neuroprotective role. Here, we performed RNA sequencing and ingenuity pathway analysis on IFNγ-treated astrocytes and found that PD-L1 was prominently expressed. Interestingly, PD-1/PD-L1 antagonism reduced apoptosis in leukocytes exposed to IFNγ-treated astrocytes in vitro. To further elucidate the role of astrocytic IFNγ signaling on the PD-1/PD-L1 axis in vivo, we induced the experimental autoimmune encephalomyelitis (EAE) model of MS in Aldh1l1-Cre(ERT2), Ifngr1(fl/fl) mice. Mice with conditional astrocytic deletion of IFNγ receptor exhibited a reduction in PD-L1 expression which corresponded to increased infiltrating leukocytes, particularly from the myeloid lineage, and exacerbated clinical disease. PD-1 agonism reduced EAE severity and CNS-infiltrating leukocytes. Importantly, PD-1 is expressed by myeloid cells surrounding MS lesions. These data support that IFNγ signaling in astrocytes diminishes inflammation during chronic autoimmunity via upregulation of PD-L1, suggesting potential therapeutic benefit for MS patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02917-4. |
format | Online Article Text |
id | pubmed-10568873 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-105688732023-10-13 Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1 Smith, Brandon C. Tinkey, Rachel A. Brock, Orion D. Mariam, Arshiya Habean, Maria L. Dutta, Ranjan Williams, Jessica L. J Neuroinflammation Research Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS). Infiltrating inflammatory immune cells perpetuate demyelination and axonal damage in the CNS and significantly contribute to pathology and clinical deficits. While the cytokine interferon (IFN)γ is classically described as deleterious in acute CNS autoimmunity, we and others have shown astrocytic IFNγ signaling also has a neuroprotective role. Here, we performed RNA sequencing and ingenuity pathway analysis on IFNγ-treated astrocytes and found that PD-L1 was prominently expressed. Interestingly, PD-1/PD-L1 antagonism reduced apoptosis in leukocytes exposed to IFNγ-treated astrocytes in vitro. To further elucidate the role of astrocytic IFNγ signaling on the PD-1/PD-L1 axis in vivo, we induced the experimental autoimmune encephalomyelitis (EAE) model of MS in Aldh1l1-Cre(ERT2), Ifngr1(fl/fl) mice. Mice with conditional astrocytic deletion of IFNγ receptor exhibited a reduction in PD-L1 expression which corresponded to increased infiltrating leukocytes, particularly from the myeloid lineage, and exacerbated clinical disease. PD-1 agonism reduced EAE severity and CNS-infiltrating leukocytes. Importantly, PD-1 is expressed by myeloid cells surrounding MS lesions. These data support that IFNγ signaling in astrocytes diminishes inflammation during chronic autoimmunity via upregulation of PD-L1, suggesting potential therapeutic benefit for MS patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02917-4. BioMed Central 2023-10-12 /pmc/articles/PMC10568873/ /pubmed/37828609 http://dx.doi.org/10.1186/s12974-023-02917-4 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This 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 Smith, Brandon C. Tinkey, Rachel A. Brock, Orion D. Mariam, Arshiya Habean, Maria L. Dutta, Ranjan Williams, Jessica L. Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1 |
title | Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1 |
title_full | Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1 |
title_fullStr | Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1 |
title_full_unstemmed | Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1 |
title_short | Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1 |
title_sort | astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via pd-l1 |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568873/ https://www.ncbi.nlm.nih.gov/pubmed/37828609 http://dx.doi.org/10.1186/s12974-023-02917-4 |
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