CXCL13/CXCR5 signalling is pivotal to preserve motor neurons in amyotrophic lateral sclerosis
Background: CXCL13 is a B and T lymphocyte chemokine that mediates neuroinflammation through its receptor CXCR5. This chemokine is highly expressed by motoneurons (MNs) in Amyotrophic Lateral Sclerosis (ALS) SOD1G93A (mSOD1) mice during the disease, particularly in fast-progressing mice. Accordingly...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-12-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396420304734 |
| _version_ | 1819294534971949056 |
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| author | Maria Chiara Trolese Alessandro Mariani Mineko Terao Massimiliano de Paola Paola Fabbrizio Francesca Sironi Mami Kurosaki Silvia Bonanno Silvia Marcuzzo Pia Bernasconi Francesca Trojsi Eleonora Aronica Caterina Bendotti Giovanni Nardo |
| author_facet | Maria Chiara Trolese Alessandro Mariani Mineko Terao Massimiliano de Paola Paola Fabbrizio Francesca Sironi Mami Kurosaki Silvia Bonanno Silvia Marcuzzo Pia Bernasconi Francesca Trojsi Eleonora Aronica Caterina Bendotti Giovanni Nardo |
| author_sort | Maria Chiara Trolese |
| collection | DOAJ |
| description | Background: CXCL13 is a B and T lymphocyte chemokine that mediates neuroinflammation through its receptor CXCR5. This chemokine is highly expressed by motoneurons (MNs) in Amyotrophic Lateral Sclerosis (ALS) SOD1G93A (mSOD1) mice during the disease, particularly in fast-progressing mice. Accordingly, in this study, we investigated the role of this chemokine in ALS. Methods: We used in vitro and in vivo experimental paradigms derived from ALS mice and patients to investigate the expression level and distribution of CXCL13/CXCR5 axis and its role in MN death and disease progression. Moreover, we compared the levels of CXCL13 in the CSF and serum of ALS patients and controls. Findings: CXCL13 and CXCR5 are overexpressed in the spinal MNs and peripheral axons in mSOD1 mice. CXCL13 inhibition in the CNS of ALS mice resulted in the exacerbation of motor impairment (n = 4/group;Mean_Diff.=27.81) and decrease survival (n = 14_Treated:19.2 ± 1.05wks, n = 17_Controls:20.2 ± 0.6wks; 95% CI: 0.4687–1.929). This was corroborated by evidence from primary spinal cultures where the inhibition or activation of CXCL13 exacerbated or prevented the MN loss. Besides, we found that CXCL13/CXCR5 axis is overexpressed in the spinal cord MNs of ALS patients, and CXCL13 levels in the CSF discriminate ALS (n = 30) from Multiple Sclerosis (n = 16) patients with a sensitivity of 97.56%. Interpretation: We hypothesise that MNs activate CXCL13 signalling to attenuate CNS inflammation and prevent the neuromuscular denervation. The low levels of CXCL13 in the CSF of ALS patients might reflect the MN dysfunction, suggesting this chemokine as a potential clinical adjunct to discriminate ALS from other neurological diseases. Funding: Vaccinex, Inc.; Regione Lombardia (TRANS-ALS) |
| first_indexed | 2024-12-24T04:27:51Z |
| format | Article |
| id | doaj.art-5ab656d8f9244ebda0d34d8887aec226 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-24T04:27:51Z |
| publishDate | 2020-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-5ab656d8f9244ebda0d34d8887aec2262022-12-21T17:15:32ZengElsevierEBioMedicine2352-39642020-12-0162103097CXCL13/CXCR5 signalling is pivotal to preserve motor neurons in amyotrophic lateral sclerosisMaria Chiara Trolese0Alessandro Mariani1Mineko Terao2Massimiliano de Paola3Paola Fabbrizio4Francesca Sironi5Mami Kurosaki6Silvia Bonanno7Silvia Marcuzzo8Pia Bernasconi9Francesca Trojsi10Eleonora Aronica11Caterina Bendotti12Giovanni Nardo13Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, ItalyLaboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, ItalyLaboratory of Molecular Biology, Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche IRCCS, Via Mario Negri 2, Milan 20156, ItalyLaboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, ItalyLaboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, ItalyLaboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, ItalyLaboratory of Molecular Biology, Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche IRCCS, Via Mario Negri 2, Milan 20156, ItalyNeurology IV-Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, Milan 20133, ItalyNeurology IV-Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, Milan 20133, ItalyNeurology IV-Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, Milan 20133, ItalyDepartment of Advanced Medical and Surgical Sciences, University of Campania 'Luigi Vanvitelli', P.zza Miraglia 2, Naples 80138, ItalyDepartment of Pathology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, NetherlandsLaboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, Italy; Corresponding authors.Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, Italy; Corresponding authors.Background: CXCL13 is a B and T lymphocyte chemokine that mediates neuroinflammation through its receptor CXCR5. This chemokine is highly expressed by motoneurons (MNs) in Amyotrophic Lateral Sclerosis (ALS) SOD1G93A (mSOD1) mice during the disease, particularly in fast-progressing mice. Accordingly, in this study, we investigated the role of this chemokine in ALS. Methods: We used in vitro and in vivo experimental paradigms derived from ALS mice and patients to investigate the expression level and distribution of CXCL13/CXCR5 axis and its role in MN death and disease progression. Moreover, we compared the levels of CXCL13 in the CSF and serum of ALS patients and controls. Findings: CXCL13 and CXCR5 are overexpressed in the spinal MNs and peripheral axons in mSOD1 mice. CXCL13 inhibition in the CNS of ALS mice resulted in the exacerbation of motor impairment (n = 4/group;Mean_Diff.=27.81) and decrease survival (n = 14_Treated:19.2 ± 1.05wks, n = 17_Controls:20.2 ± 0.6wks; 95% CI: 0.4687–1.929). This was corroborated by evidence from primary spinal cultures where the inhibition or activation of CXCL13 exacerbated or prevented the MN loss. Besides, we found that CXCL13/CXCR5 axis is overexpressed in the spinal cord MNs of ALS patients, and CXCL13 levels in the CSF discriminate ALS (n = 30) from Multiple Sclerosis (n = 16) patients with a sensitivity of 97.56%. Interpretation: We hypothesise that MNs activate CXCL13 signalling to attenuate CNS inflammation and prevent the neuromuscular denervation. The low levels of CXCL13 in the CSF of ALS patients might reflect the MN dysfunction, suggesting this chemokine as a potential clinical adjunct to discriminate ALS from other neurological diseases. Funding: Vaccinex, Inc.; Regione Lombardia (TRANS-ALS)http://www.sciencedirect.com/science/article/pii/S2352396420304734Amyotrophic lateral sclerosisSOD1G93A miceMotor neuronsImmune responseChemokines |
| spellingShingle | Maria Chiara Trolese Alessandro Mariani Mineko Terao Massimiliano de Paola Paola Fabbrizio Francesca Sironi Mami Kurosaki Silvia Bonanno Silvia Marcuzzo Pia Bernasconi Francesca Trojsi Eleonora Aronica Caterina Bendotti Giovanni Nardo CXCL13/CXCR5 signalling is pivotal to preserve motor neurons in amyotrophic lateral sclerosis EBioMedicine Amyotrophic lateral sclerosis SOD1G93A mice Motor neurons Immune response Chemokines |
| title | CXCL13/CXCR5 signalling is pivotal to preserve motor neurons in amyotrophic lateral sclerosis |
| title_full | CXCL13/CXCR5 signalling is pivotal to preserve motor neurons in amyotrophic lateral sclerosis |
| title_fullStr | CXCL13/CXCR5 signalling is pivotal to preserve motor neurons in amyotrophic lateral sclerosis |
| title_full_unstemmed | CXCL13/CXCR5 signalling is pivotal to preserve motor neurons in amyotrophic lateral sclerosis |
| title_short | CXCL13/CXCR5 signalling is pivotal to preserve motor neurons in amyotrophic lateral sclerosis |
| title_sort | cxcl13 cxcr5 signalling is pivotal to preserve motor neurons in amyotrophic lateral sclerosis |
| topic | Amyotrophic lateral sclerosis SOD1G93A mice Motor neurons Immune response Chemokines |
| url | http://www.sciencedirect.com/science/article/pii/S2352396420304734 |
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