Nógrádi, Bernát and Molnár, Kinga and Kristóf, Rebeka and Horváth, Orsolya and Huang, Yu-Ting and Ridgway, Zara and Elicegui, Amaia and Fuertes-Alvarez, Sandra and Alonso-Martin, Sonia and Szebeni, Gábor and Gémes, Nikolett and Ramadan, Abdullah and Smith, Hannah L. and Krizbai, István Adorján and Patai, Roland and Siklós, László and Klivényi, Péter and Chaytow, Helena and Gillingwater, Thomas H. (2025) The CCL2-CCR2 axis drives neuromuscular denervation in amyotrophic lateral sclerosis. NATURE COMMUNICATIONS, 16 (1). No. 7053. ISSN 2041-1723
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Abstract
Systemic immune changes have been implicated in amyotrophic lateral sclerosis (ALS), but precise mechanisms and cellular targets remain unknown. Neuromuscular junction (NMJ) denervation is another major pathophysiological event in ALS, but it remains unclear whether immune system dysregulation contributes to this process. Here, we report leukocyte and macrophage infiltration in ALS patient-derived skeletal muscle biopsies. Immune cell infiltration was replicated across the hTDP-43, TDP-43A315T (male only) and TDP43M337V mouse models, occurring from pre-symptomatic stages and targeted to NMJ-enriched muscle regions. Proteomic analysis implicated the CCL2-CCR2 axis as a driving factor. CCL2+ cells were enriched around NMJs in hTDP-43 mice, and in ALS patient skeletal muscle. Local treatment with CCL2- neutralising antibodies or normal IgG antibodies in hTDP-43 mice reduced leukocyte infiltration and ameliorated NMJ denervation. These results demonstrate that the CCL2-CCR2 axis drives immune cell infiltration targeting NMJs in ALS, identifying a potential avenue for therapeutic intervention to prevent NMJ denervation.
| Item Type: | Article |
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| Additional Information: | Funding Agency and Grant Number: Instituto de Salud Carlos III (ISCIII); European Union [PI22/00433]; ISCIII Programa Fortalece del Ministerio de Ciencia e Innovacion [FORT23/00026]; Department of Education of the Basque Country through the IKUR strategy; Osasun Saila, Eusko Jaurlaritzako [2020111032, 2023111035]; National Research, Development, and Innovation Office [FK-143326]; Ministry of Culture and Innovation of Hungary and the National Research, Development and Innovation Fund [TKP2021-EGA-32]; My Name'5 Doddie Foundation [DOD/14/32]; MND Scotland [2021/MNDS/RP/8430GILL]; Department of Education of the Basque Country [R-3825]; LifeArc; Spanish Health Institute Carlos III; Research Training Fellowship of the European Academy of Neurology; Gipuzkoa Fellow of Talent Attraction and Retention; Hungarian Eoetvoes Fellowship of the Government of Hungary; Postdoctoral Research Grant of the Albert Szent-Gyoergyi Medical School, University of Szeged; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences [BO/00582/22/8]; New National Excellence Program of the Ministry for Innovation and Technology [UNKP-23-5-SZTE-694]; [PRE_2020_1_0119]; [CD21/00066]; [2019-FELL-000010-01] Funding text: The authors would like to thank all patients who contributed to this study. They would also like to thank support staff in the IMPACT microscopy facility and the Biological Research Resources facility at the University of Edinburgh. The authors also acknowledge the microscopy support of the Cellular Imaging Laboratory at the BRC HUN-REN Core Facility and the FCBI Advanced Core Facility of Hungarian Centre of Excellence for Molecular Medicine (HCEMM). The authors would like to thank the following funders for support of the project: Instituto de Salud Carlos III (ISCIII) and the European Union (SA-M, project PI22/00433), ISCIII Programa Fortalece del Ministerio de Ciencia e Innovacion (SA-M, project FORT23/00026), Department of Education of the Basque Country through the IKUR strategy (SA-M, NEURODEGENPROT), Osasun Saila, Eusko Jaurlaritzako (SA-M, projects 2020111032, 2023111035), National Research, Development, and Innovation Office (RP, project FK-143326), TKP2021-EGA funding scheme by the Ministry of Culture and Innovation of Hungary and the National Research, Development and Innovation Fund (PK, project TKP2021-EGA-32), My Name'5 Doddie Foundation (THG and HC, project DOD/14/32), MND Scotland (THG and HC, project 2021/MNDS/RP/8430GILL), LifeArc (THG and HC, project R-3825), Research Training Fellowship of the European Academy of Neurology (BN), Hungarian Eoetvoes Fellowship of the Government of Hungary (BN), Postdoctoral Research Grant of the Albert Szent-Gyoergyi Medical School, University of Szeged (BN), Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences, (GJS, project BO/00582/22/8), New National Excellence Program of the Ministry for Innovation and Technology (GJS, project UNKP-23-5-SZTE-694), Department of Education of the Basque Country (AE, PhD fellowship PRE_2020_1_0119), Sara Borrell contract from the Spanish Health Institute Carlos III (SF-A, project CD21/00066), Gipuzkoa Fellow of Talent Attraction and Retention (SA-M, project 2019-FELL-000010-01). |
| Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 02 Sep 2025 14:34 |
| Last Modified: | 02 Sep 2025 14:34 |
| URI: | https://real.mtak.hu/id/eprint/223209 |
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