Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1
Abstract 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 inte...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-10-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02917-4 |
| _version_ | 1827633626929430528 |
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| author | Brandon C. Smith Rachel A. Tinkey Orion D. Brock Arshiya Mariam Maria L. Habean Ranjan Dutta Jessica L. Williams |
| author_facet | Brandon C. Smith Rachel A. Tinkey Orion D. Brock Arshiya Mariam Maria L. Habean Ranjan Dutta Jessica L. Williams |
| author_sort | Brandon C. Smith |
| collection | DOAJ |
| description | Abstract 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-CreERT2, 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. |
| first_indexed | 2024-03-09T15:02:12Z |
| format | Article |
| id | doaj.art-99257ce4b7c44071a83771f4345e0463 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-09T15:02:12Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-99257ce4b7c44071a83771f4345e04632023-11-26T13:51:47ZengBMCJournal of Neuroinflammation1742-20942023-10-0120111410.1186/s12974-023-02917-4Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1Brandon C. Smith0Rachel A. Tinkey1Orion D. Brock2Arshiya Mariam3Maria L. Habean4Ranjan Dutta5Jessica L. Williams6Department of Neurosciences, Lerner Research Institute, Cleveland ClinicDepartment of Neurosciences, Lerner Research Institute, Cleveland ClinicDepartment of Neurosciences, Lerner Research Institute, Cleveland ClinicDepartment of Quantitative Health Sciences, Lerner Research Institute, Cleveland ClinicDepartment of Neurosciences, Lerner Research Institute, Cleveland ClinicDepartment of Neurosciences, Lerner Research Institute, Cleveland ClinicDepartment of Neurosciences, Lerner Research Institute, Cleveland ClinicAbstract 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-CreERT2, 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.https://doi.org/10.1186/s12974-023-02917-4Multiple sclerosisAstrocyteInterferon |
| spellingShingle | Brandon C. Smith Rachel A. Tinkey Orion D. Brock Arshiya Mariam Maria L. Habean Ranjan Dutta Jessica L. Williams Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1 Journal of Neuroinflammation Multiple sclerosis Astrocyte Interferon |
| 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 | Multiple sclerosis Astrocyte Interferon |
| url | https://doi.org/10.1186/s12974-023-02917-4 |
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