C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9
Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, with additional pathophysiological involvement of non-neuronal cells such as microglia. The commonest ALS-associated genetic variant is a hexanucleotide repeat expansion (HRE)...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41603-0 |
| _version_ | 1797558511885877248 |
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| author | Björn F. Vahsen Sumedha Nalluru Georgia R. Morgan Lucy Farrimond Emily Carroll Yinyan Xu Kaitlyn M. L. Cramb Benazir Amein Jakub Scaber Antigoni Katsikoudi Ana Candalija Mireia Carcolé Ruxandra Dafinca Adrian M. Isaacs Richard Wade-Martins Elizabeth Gray Martin R. Turner Sally A. Cowley Kevin Talbot |
| author_facet | Björn F. Vahsen Sumedha Nalluru Georgia R. Morgan Lucy Farrimond Emily Carroll Yinyan Xu Kaitlyn M. L. Cramb Benazir Amein Jakub Scaber Antigoni Katsikoudi Ana Candalija Mireia Carcolé Ruxandra Dafinca Adrian M. Isaacs Richard Wade-Martins Elizabeth Gray Martin R. Turner Sally A. Cowley Kevin Talbot |
| author_sort | Björn F. Vahsen |
| collection | DOAJ |
| description | Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, with additional pathophysiological involvement of non-neuronal cells such as microglia. The commonest ALS-associated genetic variant is a hexanucleotide repeat expansion (HRE) mutation in C9orf72. Here, we study its consequences for microglial function using human iPSC-derived microglia. By RNA-sequencing, we identify enrichment of pathways associated with immune cell activation and cyto-/chemokines in C9orf72 HRE mutant microglia versus healthy controls, most prominently after LPS priming. Specifically, LPS-primed C9orf72 HRE mutant microglia show consistently increased expression and release of matrix metalloproteinase-9 (MMP9). LPS-primed C9orf72 HRE mutant microglia are toxic to co-cultured healthy motor neurons, which is ameliorated by concomitant application of an MMP9 inhibitor. Finally, we identify release of dipeptidyl peptidase-4 (DPP4) as a marker for MMP9-dependent microglial dysregulation in co-culture. These results demonstrate cellular dysfunction of C9orf72 HRE mutant microglia, and a non-cell-autonomous role in driving C9orf72-ALS pathophysiology in motor neurons through MMP9 signaling. |
| first_indexed | 2024-03-10T17:32:25Z |
| format | Article |
| id | doaj.art-3d51552885d24a2f94bd75e36ffa3438 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:32:25Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-3d51552885d24a2f94bd75e36ffa34382023-11-20T09:58:35ZengNature PortfolioNature Communications2041-17232023-09-0114111610.1038/s41467-023-41603-0C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9Björn F. Vahsen0Sumedha Nalluru1Georgia R. Morgan2Lucy Farrimond3Emily Carroll4Yinyan Xu5Kaitlyn M. L. Cramb6Benazir Amein7Jakub Scaber8Antigoni Katsikoudi9Ana Candalija10Mireia Carcolé11Ruxandra Dafinca12Adrian M. Isaacs13Richard Wade-Martins14Elizabeth Gray15Martin R. Turner16Sally A. Cowley17Kevin Talbot18Oxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe HospitalOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe HospitalOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe HospitalOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe HospitalOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe HospitalOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe HospitalKavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin BuildingOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe HospitalOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe HospitalKavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin BuildingOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe HospitalUK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of NeurologyOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe HospitalUK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of NeurologyKavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin BuildingOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe HospitalOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe HospitalJames and Lillian Martin Centre for Stem Cell Research, Sir William Dunn School of Pathology, University of OxfordOxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe HospitalAbstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, with additional pathophysiological involvement of non-neuronal cells such as microglia. The commonest ALS-associated genetic variant is a hexanucleotide repeat expansion (HRE) mutation in C9orf72. Here, we study its consequences for microglial function using human iPSC-derived microglia. By RNA-sequencing, we identify enrichment of pathways associated with immune cell activation and cyto-/chemokines in C9orf72 HRE mutant microglia versus healthy controls, most prominently after LPS priming. Specifically, LPS-primed C9orf72 HRE mutant microglia show consistently increased expression and release of matrix metalloproteinase-9 (MMP9). LPS-primed C9orf72 HRE mutant microglia are toxic to co-cultured healthy motor neurons, which is ameliorated by concomitant application of an MMP9 inhibitor. Finally, we identify release of dipeptidyl peptidase-4 (DPP4) as a marker for MMP9-dependent microglial dysregulation in co-culture. These results demonstrate cellular dysfunction of C9orf72 HRE mutant microglia, and a non-cell-autonomous role in driving C9orf72-ALS pathophysiology in motor neurons through MMP9 signaling.https://doi.org/10.1038/s41467-023-41603-0 |
| spellingShingle | Björn F. Vahsen Sumedha Nalluru Georgia R. Morgan Lucy Farrimond Emily Carroll Yinyan Xu Kaitlyn M. L. Cramb Benazir Amein Jakub Scaber Antigoni Katsikoudi Ana Candalija Mireia Carcolé Ruxandra Dafinca Adrian M. Isaacs Richard Wade-Martins Elizabeth Gray Martin R. Turner Sally A. Cowley Kevin Talbot C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9 Nature Communications |
| title | C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9 |
| title_full | C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9 |
| title_fullStr | C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9 |
| title_full_unstemmed | C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9 |
| title_short | C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9 |
| title_sort | c9orf72 als human ipsc microglia are pro inflammatory and toxic to co cultured motor neurons via mmp9 |
| url | https://doi.org/10.1038/s41467-023-41603-0 |
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