SIRT1 inactivation switches reactive astrocytes to an antiinflammatory phenotype in CNS autoimmunity
Astrocytes are highly heterogeneous in their phenotype and function, which contributes to CNS disease, repair, and aging; however, the molecular mechanism of their functional states remains largely unknown. Here, we show that activation of sirtuin 1 (SIRT1), a protein deacetylase, played an importan...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-11-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI151803 |
| _version_ | 1797634507081252864 |
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| author | Weifeng Zhang Dan Xiao Xing Li Yuan Zhang Javad Rasouli Giacomo Casella Alexandra Boehm Daniel Hwang Larissa L.W. Ishikawa Rodolfo Thome Bogoljub Ciric Mark T. Curtis Abdolmohamad Rostami Guang-Xian Zhang |
| author_facet | Weifeng Zhang Dan Xiao Xing Li Yuan Zhang Javad Rasouli Giacomo Casella Alexandra Boehm Daniel Hwang Larissa L.W. Ishikawa Rodolfo Thome Bogoljub Ciric Mark T. Curtis Abdolmohamad Rostami Guang-Xian Zhang |
| author_sort | Weifeng Zhang |
| collection | DOAJ |
| description | Astrocytes are highly heterogeneous in their phenotype and function, which contributes to CNS disease, repair, and aging; however, the molecular mechanism of their functional states remains largely unknown. Here, we show that activation of sirtuin 1 (SIRT1), a protein deacetylase, played an important role in the detrimental actions of reactive astrocytes, whereas its inactivation conferred these cells with antiinflammatory functions that inhibited the production of proinflammatory mediators by myeloid cells and microglia and promoted the differentiation of oligodendrocyte progenitor cells. Mice with astrocyte-specific Sirt1 knockout (Sirt1–/–) had suppressed progression of experimental autoimmune encephalomyelitis (EAE), an animal model of CNS inflammatory demyelinating disease. Ongoing EAE was also suppressed when Sirt1 expression in astrocytes was diminished by a CRISPR/Cas vector, resulting in reduced demyelination, decreased numbers of T cells, and an increased rate of IL-10–producing macrophages and microglia in the CNS, whereas the peripheral immune response remained unaffected. Mechanistically, Sirt1–/– astrocytes expressed a range of nuclear factor erythroid–derived 2–like 2 (Nfe2l2) target genes, and Nfe2l2 deficiency shifted the beneficial action of Sirt1–/– astrocytes to a detrimental one. These findings identify an approach for switching the functional state of reactive astrocytes that will facilitate the development of astrocyte-targeting therapies for inflammatory neurodegenerative diseases such as multiple sclerosis. |
| first_indexed | 2024-03-11T12:09:45Z |
| format | Article |
| id | doaj.art-6a88e9f7e5d74a7c842c4e33e2a93d55 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:45Z |
| publishDate | 2022-11-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-6a88e9f7e5d74a7c842c4e33e2a93d552023-11-07T16:19:36ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-11-0113222SIRT1 inactivation switches reactive astrocytes to an antiinflammatory phenotype in CNS autoimmunityWeifeng ZhangDan XiaoXing LiYuan ZhangJavad RasouliGiacomo CasellaAlexandra BoehmDaniel HwangLarissa L.W. IshikawaRodolfo ThomeBogoljub CiricMark T. CurtisAbdolmohamad RostamiGuang-Xian ZhangAstrocytes are highly heterogeneous in their phenotype and function, which contributes to CNS disease, repair, and aging; however, the molecular mechanism of their functional states remains largely unknown. Here, we show that activation of sirtuin 1 (SIRT1), a protein deacetylase, played an important role in the detrimental actions of reactive astrocytes, whereas its inactivation conferred these cells with antiinflammatory functions that inhibited the production of proinflammatory mediators by myeloid cells and microglia and promoted the differentiation of oligodendrocyte progenitor cells. Mice with astrocyte-specific Sirt1 knockout (Sirt1–/–) had suppressed progression of experimental autoimmune encephalomyelitis (EAE), an animal model of CNS inflammatory demyelinating disease. Ongoing EAE was also suppressed when Sirt1 expression in astrocytes was diminished by a CRISPR/Cas vector, resulting in reduced demyelination, decreased numbers of T cells, and an increased rate of IL-10–producing macrophages and microglia in the CNS, whereas the peripheral immune response remained unaffected. Mechanistically, Sirt1–/– astrocytes expressed a range of nuclear factor erythroid–derived 2–like 2 (Nfe2l2) target genes, and Nfe2l2 deficiency shifted the beneficial action of Sirt1–/– astrocytes to a detrimental one. These findings identify an approach for switching the functional state of reactive astrocytes that will facilitate the development of astrocyte-targeting therapies for inflammatory neurodegenerative diseases such as multiple sclerosis.https://doi.org/10.1172/JCI151803AutoimmunityInflammation |
| spellingShingle | Weifeng Zhang Dan Xiao Xing Li Yuan Zhang Javad Rasouli Giacomo Casella Alexandra Boehm Daniel Hwang Larissa L.W. Ishikawa Rodolfo Thome Bogoljub Ciric Mark T. Curtis Abdolmohamad Rostami Guang-Xian Zhang SIRT1 inactivation switches reactive astrocytes to an antiinflammatory phenotype in CNS autoimmunity The Journal of Clinical Investigation Autoimmunity Inflammation |
| title | SIRT1 inactivation switches reactive astrocytes to an antiinflammatory phenotype in CNS autoimmunity |
| title_full | SIRT1 inactivation switches reactive astrocytes to an antiinflammatory phenotype in CNS autoimmunity |
| title_fullStr | SIRT1 inactivation switches reactive astrocytes to an antiinflammatory phenotype in CNS autoimmunity |
| title_full_unstemmed | SIRT1 inactivation switches reactive astrocytes to an antiinflammatory phenotype in CNS autoimmunity |
| title_short | SIRT1 inactivation switches reactive astrocytes to an antiinflammatory phenotype in CNS autoimmunity |
| title_sort | sirt1 inactivation switches reactive astrocytes to an antiinflammatory phenotype in cns autoimmunity |
| topic | Autoimmunity Inflammation |
| url | https://doi.org/10.1172/JCI151803 |
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