Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients
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| Názov: | Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients |
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| Autori: | Laura Krumm, Tatyana Pozner, Naime Zagha, Roland Coras, Philipp Arnold, Thanos Tsaktanis, Kathryn Scherpelz, Marie Y. Davis, Johanna Kaindl, Iris Stolzer, Patrick Süß, Mukhran Khundadze, Christian A. Hübner, Markus J. Riemenschneider, Jonathan Baets, Claudia Günther, Suman Jayadev, Veit Rothhammer, Florian Krach, Jürgen Winkler, Beate Winner, Martin Regensburger |
| Zdroj: | Acta Neuropathol Acta neuropathologica |
| Informácie o vydavateľovi: | Springer Science and Business Media LLC, 2024. |
| Rok vydania: | 2024 |
| Predmety: | Autosomal-recessive hereditary spastic paraplegia, Mutation [MeSH], Disease-associated microglia, Humans [MeSH], Inflammation, Spastic Paraplegia, Hereditary/pathology [MeSH], Animals [MeSH], IFNγ/ STAT1 signaling, Spastic Paraplegia, Hereditary/genetics [MeSH], Multisystem neurodegeneration, Neuroinflammatory Diseases [MeSH], Mice [MeSH], Proteins/genetics [MeSH], Original Paper, Neurons/pathology [MeSH], Induced microglia-like cells, Neurons, 0301 basic medicine, 0303 health sciences, Spastic Paraplegia, Hereditary, Proteins, 3. Good health, Mice, 03 medical and health sciences, Neuroinflammatory Diseases, Mutation, Animals, Humans, Human medicine |
| Popis: | Biallelic loss of SPG11 function constitutes the most frequent cause of complicated autosomal recessive hereditary spastic paraplegia (HSP) with thin corpus callosum, resulting in progressive multisystem neurodegeneration. While the impact of neuroinflammation is an emerging and potentially treatable aspect in neurodegenerative diseases and leukodystrophies, the role of immune cells in SPG11–HSP patients is unknown. Here, we performed a comprehensive immunological characterization of SPG11–HSP, including examination of three human postmortem brain donations, immunophenotyping of patients’ peripheral blood cells and patient-specific induced pluripotent stem cell-derived microglia-like cells (iMGL). We delineate a previously unknown role of innate immunity in SPG11–HSP. Neuropathological analysis of SPG11–HSP patient brain tissue revealed profound microgliosis in areas of neurodegeneration, downregulation of homeostatic microglial markers and cell-intrinsic accumulation of lipids and lipofuscin in IBA1+ cells. In a larger cohort of SPG11–HSP patients, the ratio of peripheral classical and intermediate monocytes was increased, along with increased serum levels of IL-6 that correlated with disease severity. Stimulation of patient-specific iMGLs with IFNγ led to increased phagocytic activity compared to control iMGL as well as increased upregulation and release of proinflammatory cytokines and chemokines, such as CXCL10. On a molecular basis, we identified increased STAT1 phosphorylation as mechanism connecting IFNγ-mediated immune hyperactivation and SPG11 loss of function. STAT1 expression was increased both in human postmortem brain tissue and in an Spg11–/– mouse model. Application of an STAT1 inhibitor decreased CXCL10 production in SPG11 iMGL and rescued their toxic effect on SPG11 neurons. Our data establish neuroinflammation as a novel disease mechanism in SPG11–HSP patients and constitute the first description of myeloid cell/ microglia activation in human SPG11–HSP. IFNγ/ STAT1-mediated neurotoxic effects of hyperreactive microglia upon SPG11 loss of function indicate that immunomodulation strategies may slow down disease progression. |
| Druh dokumentu: | Article Other literature type |
| Jazyk: | English |
| ISSN: | 1432-0533 0001-6322 |
| DOI: | 10.1007/s00401-023-02675-w |
| Prístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/38305941 https://hdl.handle.net/10067/2038820151162165141 https://repository.uantwerpen.be/docstore/d:irua:22333 https://repository.publisso.de/resource/frl:6519667 |
| Rights: | CC BY |
| Prístupové číslo: | edsair.doi.dedup.....c1787734e9f9d8b4778ad9817f6d76ea |
| Databáza: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Biallelic loss of SPG11 function constitutes the most frequent cause of complicated autosomal recessive hereditary spastic paraplegia (HSP) with thin corpus callosum, resulting in progressive multisystem neurodegeneration. While the impact of neuroinflammation is an emerging and potentially treatable aspect in neurodegenerative diseases and leukodystrophies, the role of immune cells in SPG11–HSP patients is unknown. Here, we performed a comprehensive immunological characterization of SPG11–HSP, including examination of three human postmortem brain donations, immunophenotyping of patients’ peripheral blood cells and patient-specific induced pluripotent stem cell-derived microglia-like cells (iMGL). We delineate a previously unknown role of innate immunity in SPG11–HSP. Neuropathological analysis of SPG11–HSP patient brain tissue revealed profound microgliosis in areas of neurodegeneration, downregulation of homeostatic microglial markers and cell-intrinsic accumulation of lipids and lipofuscin in IBA1+ cells. In a larger cohort of SPG11–HSP patients, the ratio of peripheral classical and intermediate monocytes was increased, along with increased serum levels of IL-6 that correlated with disease severity. Stimulation of patient-specific iMGLs with IFNγ led to increased phagocytic activity compared to control iMGL as well as increased upregulation and release of proinflammatory cytokines and chemokines, such as CXCL10. On a molecular basis, we identified increased STAT1 phosphorylation as mechanism connecting IFNγ-mediated immune hyperactivation and SPG11 loss of function. STAT1 expression was increased both in human postmortem brain tissue and in an Spg11–/– mouse model. Application of an STAT1 inhibitor decreased CXCL10 production in SPG11 iMGL and rescued their toxic effect on SPG11 neurons. Our data establish neuroinflammation as a novel disease mechanism in SPG11–HSP patients and constitute the first description of myeloid cell/ microglia activation in human SPG11–HSP. IFNγ/ STAT1-mediated neurotoxic effects of hyperreactive microglia upon SPG11 loss of function indicate that immunomodulation strategies may slow down disease progression. |
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| ISSN: | 14320533 00016322 |
| DOI: | 10.1007/s00401-023-02675-w |