Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage
Abstract During intracerebral hemorrhage (ICH), hematoma formation at the site of blood vessel damage results in local mechanical injury. Subsequently, erythrocytes lyse to release hemoglobin and heme, which act as neurotoxins and induce inflammation and secondary brain injury, resulting in severe n...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05520-2 |
| _version_ | 1797863433301917696 |
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| author | Kuan-Yin Tseng Vassilis Stratoulias Wei-Fen Hu Jui-Sheng Wu Vicki Wang Yuan-Hao Chen Anna Seelbach Henri J. Huttunen Natalia Kulesskaya Cheng-Yoong Pang Jian-Liang Chou Maria Lindahl Mart Saarma Li-Chuan Huang Mikko Airavaara Hock-Kean Liew |
| author_facet | Kuan-Yin Tseng Vassilis Stratoulias Wei-Fen Hu Jui-Sheng Wu Vicki Wang Yuan-Hao Chen Anna Seelbach Henri J. Huttunen Natalia Kulesskaya Cheng-Yoong Pang Jian-Liang Chou Maria Lindahl Mart Saarma Li-Chuan Huang Mikko Airavaara Hock-Kean Liew |
| author_sort | Kuan-Yin Tseng |
| collection | DOAJ |
| description | Abstract During intracerebral hemorrhage (ICH), hematoma formation at the site of blood vessel damage results in local mechanical injury. Subsequently, erythrocytes lyse to release hemoglobin and heme, which act as neurotoxins and induce inflammation and secondary brain injury, resulting in severe neurological deficits. Accelerating hematoma resorption and mitigating hematoma-induced brain edema by modulating immune cells has potential as a novel therapeutic strategy for functional recovery after ICH. Here, we show that intracerebroventricular administration of recombinant human cerebral dopamine neurotrophic factor (rhCDNF) accelerates hemorrhagic lesion resolution, reduces peri-focal edema, and improves neurological outcomes in an animal model of collagenase-induced ICH. We demonstrate that CDNF acts on microglia/macrophages in the hemorrhagic striatum by promoting scavenger receptor expression, enhancing erythrophagocytosis and increasing anti-inflammatory mediators while suppressing the production of pro-inflammatory cytokines. Administration of rhCDNF results in upregulation of the Nrf2-HO-1 pathway, but alleviation of oxidative stress and unfolded protein responses in the perihematomal area. Finally, we demonstrate that intravenous delivery of rhCDNF has beneficial effects in an animal model of ICH and that systemic application promotes scavenging by the brain’s myeloid cells for the treatment of ICH. |
| first_indexed | 2024-04-09T22:35:30Z |
| format | Article |
| id | doaj.art-e5091f6de8f64d6aa9ee0c7414b369b1 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-09T22:35:30Z |
| publishDate | 2023-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-e5091f6de8f64d6aa9ee0c7414b369b12023-03-22T12:32:34ZengNature Publishing GroupCell Death and Disease2041-48892023-02-0114212010.1038/s41419-022-05520-2Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhageKuan-Yin Tseng0Vassilis Stratoulias1Wei-Fen Hu2Jui-Sheng Wu3Vicki Wang4Yuan-Hao Chen5Anna Seelbach6Henri J. Huttunen7Natalia Kulesskaya8Cheng-Yoong Pang9Jian-Liang Chou10Maria Lindahl11Mart Saarma12Li-Chuan Huang13Mikko Airavaara14Hock-Kean Liew15Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical CenterNeuroscience Center, HiLIFE, Haartmaninkatu 8, FI-00014, University of HelsinkiPhD Program in Pharmacology and Toxicology, Tzu Chi UniversityDepartment of Neurological Surgery, Tri-Service General Hospital and National Defense Medical CenterDepartment of Neurological Surgery, Tri-Service General Hospital and National Defense Medical CenterDepartment of Neurological Surgery, Tri-Service General Hospital and National Defense Medical CenterNeuroscience Center, HiLIFE, Haartmaninkatu 8, FI-00014, University of HelsinkiHerantis Pharma Ltd, PlcHerantis Pharma Ltd, PlcInstitute of Medical Sciences, Tzu Chi UniversityGraduate Institute of Medical Sciences, National Defense Medical CenterInstitute of Biotechnology, HiLIFE, Viikinkaari 5D, FI-00014, University of HelsinkiInstitute of Biotechnology, HiLIFE, Viikinkaari 5D, FI-00014, University of HelsinkiDepartment of Medical Imaging, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical FoundationNeuroscience Center, HiLIFE, Haartmaninkatu 8, FI-00014, University of HelsinkiPhD Program in Pharmacology and Toxicology, Tzu Chi UniversityAbstract During intracerebral hemorrhage (ICH), hematoma formation at the site of blood vessel damage results in local mechanical injury. Subsequently, erythrocytes lyse to release hemoglobin and heme, which act as neurotoxins and induce inflammation and secondary brain injury, resulting in severe neurological deficits. Accelerating hematoma resorption and mitigating hematoma-induced brain edema by modulating immune cells has potential as a novel therapeutic strategy for functional recovery after ICH. Here, we show that intracerebroventricular administration of recombinant human cerebral dopamine neurotrophic factor (rhCDNF) accelerates hemorrhagic lesion resolution, reduces peri-focal edema, and improves neurological outcomes in an animal model of collagenase-induced ICH. We demonstrate that CDNF acts on microglia/macrophages in the hemorrhagic striatum by promoting scavenger receptor expression, enhancing erythrophagocytosis and increasing anti-inflammatory mediators while suppressing the production of pro-inflammatory cytokines. Administration of rhCDNF results in upregulation of the Nrf2-HO-1 pathway, but alleviation of oxidative stress and unfolded protein responses in the perihematomal area. Finally, we demonstrate that intravenous delivery of rhCDNF has beneficial effects in an animal model of ICH and that systemic application promotes scavenging by the brain’s myeloid cells for the treatment of ICH.https://doi.org/10.1038/s41419-022-05520-2 |
| spellingShingle | Kuan-Yin Tseng Vassilis Stratoulias Wei-Fen Hu Jui-Sheng Wu Vicki Wang Yuan-Hao Chen Anna Seelbach Henri J. Huttunen Natalia Kulesskaya Cheng-Yoong Pang Jian-Liang Chou Maria Lindahl Mart Saarma Li-Chuan Huang Mikko Airavaara Hock-Kean Liew Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage Cell Death and Disease |
| title | Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage |
| title_full | Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage |
| title_fullStr | Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage |
| title_full_unstemmed | Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage |
| title_short | Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage |
| title_sort | augmenting hematoma scavenging capacity of innate immune cells by cdnf reduces brain injury and promotes functional recovery after intracerebral hemorrhage |
| url | https://doi.org/10.1038/s41419-022-05520-2 |
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