ER stress induced immunopathology involving complement in CADASIL: implications for therapeutics
Abstract Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 mutations. Typical CADASIL is characterised by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small arteries. Arteriolar vascular smoo...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-05-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-023-01558-1 |
| _version_ | 1797827285009563648 |
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| author | Mahmod Panahi Yoshiki Hase Xavier Gallart-Palau Sumonto Mitra Atsushi Watanabe Roger C Low Yumi Yamamoto Diego Sepulveda-Falla Atticus H Hainsworth Masafumi Ihara Siu Kwan Sze Matti Viitanen Homira Behbahani Raj N Kalaria |
| author_facet | Mahmod Panahi Yoshiki Hase Xavier Gallart-Palau Sumonto Mitra Atsushi Watanabe Roger C Low Yumi Yamamoto Diego Sepulveda-Falla Atticus H Hainsworth Masafumi Ihara Siu Kwan Sze Matti Viitanen Homira Behbahani Raj N Kalaria |
| author_sort | Mahmod Panahi |
| collection | DOAJ |
| description | Abstract Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 mutations. Typical CADASIL is characterised by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small arteries. Arteriolar vascular smooth muscle cells (VSMCs) are the key target in CADASIL, but the potential mechanisms involved in their degeneration are still unclear. Focusing on cerebral microvessels in the frontal and anterior temporal lobes and the basal ganglia, we used advanced proteomic and immunohistochemical methods to explore the extent of inflammatory and immune responses in CADASIL subjects compared to similar age normal and other disease controls. There was variable loss of VSMC in medial layers of arteries in white matter as well as the cortex, that could not be distinguished whether NOTCH3 mutations were in the epidermal growth factor (EGFr) domains 1–6 or EGFr7-34. Proteomics of isolated cerebral microvessels showed alterations in several proteins, many associated with endoplasmic reticulum (ER) stress including heat shock proteins. Cerebral vessels with sparsely populated VSMCs also attracted robust accrual of perivascular microglia/macrophages in order CD45+ > CD163+ > CD68+cells, with > 60% of vessel walls exhibiting intercellular adhesion molecule-1 (ICAM-1) immunoreactivity. Functional VSMC cultures bearing the NOTCH3 Arg133Cys mutation showed increased gene expression of the pro-inflammatory cytokine interleukin 6 and ICAM-1 by 16- and 50-fold, respectively. We further found evidence for activation of the alternative pathway of complement. Immunolocalisation of complement Factor B, C3d and C5-9 terminal complex but not C1q was apparent in ~ 70% of cerebral vessels. Increased complement expression was corroborated in > 70% of cultured VSMCs bearing the Arg133Cys mutation independent of N3ECD immunoreactivity. Our observations suggest that ER stress and other cellular features associated with arteriolar VSMC damage instigate robust localized inflammatory and immune responses in CADASIL. Our study has important implications for immunomodulation approaches to counter the characteristic arteriopathy of CADASIL. |
| first_indexed | 2024-04-09T12:45:51Z |
| format | Article |
| id | doaj.art-11dce6bfaaa44fa2b8315fb967bc1c18 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-04-09T12:45:51Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-11dce6bfaaa44fa2b8315fb967bc1c182023-05-14T11:31:07ZengBMCActa Neuropathologica Communications2051-59602023-05-0111112010.1186/s40478-023-01558-1ER stress induced immunopathology involving complement in CADASIL: implications for therapeuticsMahmod Panahi0Yoshiki Hase1Xavier Gallart-Palau2Sumonto Mitra3Atsushi Watanabe4Roger C Low5Yumi Yamamoto6Diego Sepulveda-Falla7Atticus H Hainsworth8Masafumi Ihara9Siu Kwan Sze10Matti Viitanen11Homira Behbahani12Raj N Kalaria13Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Clinical Geriatrics, Karolinska InstitutetTranslational and Clinical Research Institute, Campus for Ageing and Vitality, Newcastle UniversityBiomedical Research Institute of Lleida (IRBLLEIDA) - +Pec Proteomics Research Group (+PPRG) - Neuroscience Area, University Hospital Arnau de Vilanova (HUAV) - Department of Psychology, University of Lleida (UdL)Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Clinical Geriatrics, Karolinska InstitutetEquipment Management Division, Center for Core Facility Administration, Research Institute, National Center for Geriatrics and Gerontology (NCGG)Translational and Clinical Research Institute, Campus for Ageing and Vitality, Newcastle UniversityDepartment of Molecular Innovation in Lipidemiology and Department of Neurology, National Cerebral and Cardiovascular CenterMolecular Neuropathology of Alzheimer’s Disease, Institute of Neuropathology, University Medical Center Hamburg-EppendorfMolecular and Clinical Sciences, St George’s University of LondonDepartment of Molecular Innovation in Lipidemiology and Department of Neurology, National Cerebral and Cardiovascular CenterFaculty of Applied Health Sciences, Brock UniversityDepartment of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Clinical Geriatrics, Karolinska InstitutetDepartment of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Clinical Geriatrics, Karolinska InstitutetTranslational and Clinical Research Institute, Campus for Ageing and Vitality, Newcastle UniversityAbstract Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 mutations. Typical CADASIL is characterised by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small arteries. Arteriolar vascular smooth muscle cells (VSMCs) are the key target in CADASIL, but the potential mechanisms involved in their degeneration are still unclear. Focusing on cerebral microvessels in the frontal and anterior temporal lobes and the basal ganglia, we used advanced proteomic and immunohistochemical methods to explore the extent of inflammatory and immune responses in CADASIL subjects compared to similar age normal and other disease controls. There was variable loss of VSMC in medial layers of arteries in white matter as well as the cortex, that could not be distinguished whether NOTCH3 mutations were in the epidermal growth factor (EGFr) domains 1–6 or EGFr7-34. Proteomics of isolated cerebral microvessels showed alterations in several proteins, many associated with endoplasmic reticulum (ER) stress including heat shock proteins. Cerebral vessels with sparsely populated VSMCs also attracted robust accrual of perivascular microglia/macrophages in order CD45+ > CD163+ > CD68+cells, with > 60% of vessel walls exhibiting intercellular adhesion molecule-1 (ICAM-1) immunoreactivity. Functional VSMC cultures bearing the NOTCH3 Arg133Cys mutation showed increased gene expression of the pro-inflammatory cytokine interleukin 6 and ICAM-1 by 16- and 50-fold, respectively. We further found evidence for activation of the alternative pathway of complement. Immunolocalisation of complement Factor B, C3d and C5-9 terminal complex but not C1q was apparent in ~ 70% of cerebral vessels. Increased complement expression was corroborated in > 70% of cultured VSMCs bearing the Arg133Cys mutation independent of N3ECD immunoreactivity. Our observations suggest that ER stress and other cellular features associated with arteriolar VSMC damage instigate robust localized inflammatory and immune responses in CADASIL. Our study has important implications for immunomodulation approaches to counter the characteristic arteriopathy of CADASIL.https://doi.org/10.1186/s40478-023-01558-1CADASILComplementInterleukin 6Intracellular adhesion moleculeStrokeVascular smooth muscle cells |
| spellingShingle | Mahmod Panahi Yoshiki Hase Xavier Gallart-Palau Sumonto Mitra Atsushi Watanabe Roger C Low Yumi Yamamoto Diego Sepulveda-Falla Atticus H Hainsworth Masafumi Ihara Siu Kwan Sze Matti Viitanen Homira Behbahani Raj N Kalaria ER stress induced immunopathology involving complement in CADASIL: implications for therapeutics Acta Neuropathologica Communications CADASIL Complement Interleukin 6 Intracellular adhesion molecule Stroke Vascular smooth muscle cells |
| title | ER stress induced immunopathology involving complement in CADASIL: implications for therapeutics |
| title_full | ER stress induced immunopathology involving complement in CADASIL: implications for therapeutics |
| title_fullStr | ER stress induced immunopathology involving complement in CADASIL: implications for therapeutics |
| title_full_unstemmed | ER stress induced immunopathology involving complement in CADASIL: implications for therapeutics |
| title_short | ER stress induced immunopathology involving complement in CADASIL: implications for therapeutics |
| title_sort | er stress induced immunopathology involving complement in cadasil implications for therapeutics |
| topic | CADASIL Complement Interleukin 6 Intracellular adhesion molecule Stroke Vascular smooth muscle cells |
| url | https://doi.org/10.1186/s40478-023-01558-1 |
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