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Intracellular complement factor H protects neurons during CNS inflammation.

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Τίτλος: Intracellular complement factor H protects neurons during CNS inflammation.
Συγγραφείς: Mayer C; Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Woo MS; Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Sonner JK; Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Binkle-Ladisch L; Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Fischbach F; Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Sekol P; Division of Neuroimmunology, Department of Neurology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Smith MD; Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Lucas-Ruiz F; Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Group of Experimental Ophthalmology, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca) and Ophthalmology Department, Universidad de Murcia, Murcia, Spain., Manteufel D; Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Mattern KM; Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Pfeffer LK; Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Guo Y; III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Siebels B; Section Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Miguela A; Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Neurodegeneration and Neuroinflammation Group, Girona Biomedical Research Institute (IDIBG-CERCA), Salt, Spain., Vieira V; Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Meurs N; Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Bauer S; Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Schwarz S; Division of Neuroimmunology, Department of Neurology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Wulf S; Institute of Pathology, Nephropathology Section, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Mühlig AK; III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; University Children's Research@Kinder-UKE, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Engler JB; Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Conrad M; Institute of Metabolism and Cell Death, Molecular Targets and Therapeutics Center, Helmholtz Munich, Neuherberg, Germany.; Translational Redox Biology, Technical University of Munich (TUM), TUM Natural School of Sciences, Garching, Germany., Bareyre FM; Institute of Clinical Neuroimmunology, University Hospital LMU Munich, Munich, Germany., Wiech T; Institute of Pathology, Nephropathology Section, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Krasemann S; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Glatzel M; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Zipfel PF; Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany., Freiwald T; III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Calabresi PA; Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Schirmer L; Division of Neuroimmunology, Department of Neurology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.; Mannheim Center for Translational Neuroscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.; Mannheim Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.; Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany., Friese MA; Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. manuel.friese@zmnh.uni-hamburg.de.; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. manuel.friese@zmnh.uni-hamburg.de.
Πηγή: Nature [Nature] 2026 Oct; Vol. 658 (8136), pp. 765-773. Date of Electronic Publication: 2026 Sep 02.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
Imprint Name(s): Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.
Ιατρικοί όροι (MeSH): Complement Factor H*/metabolism , Complement Factor H*/chemistry , Complement Factor H*/genetics , Retinal Ganglion Cells*/pathology , Retinal Ganglion Cells*/metabolism , Multiple Sclerosis*/pathology , Multiple Sclerosis*/metabolism , Inflammation*/pathology , Inflammation*/metabolism , Central Nervous System*/pathology , Neurons*/metabolism , Neurons*/pathology , Neuroprotection*, Reactive Oxygen Species/metabolism ; Complement C3/metabolism ; Complement C3/deficiency ; Humans ; Animals ; Female ; Mice ; Male ; Oxidative Stress ; Lipid Peroxidation ; Single-Cell Analysis
Περίληψη: Neurodegeneration is a major driver of disability in multiple sclerosis (MS), the most common chronic inflammatory disease of the central nervous system (CNS)1. Retinal ganglion cells (RGCs), a heterogeneous neuronal population in the eye, undergo degeneration in MS and provide a model to study neuronal subtype-specific resilience to inflammatory injury2. However, the neuron-intrinsic mechanisms underlying differential vulnerability remain unclear. Here we identify a neuroprotective role for intracellular complement factor H (CFH) in neurons. Using single-nucleus RNA-sequencing analysis of RGCs from donors with MS and control individuals, we found that CFH expression was strongly correlated with intrinsic resilience to RGC degeneration. Mechanistically, CFH was induced in retinal and other CNS neurons in response to inflammatory and oxidative stress, where it limited reactive oxygen species accumulation and lipid peroxidation. CFH localized to the endoplasmic reticulum, a major site of lipid peroxidation during neuronal ferroptosis. Its protective activity was dependent on its C-terminal SCR20 domain, was independent of CFH secretion and was preserved in the absence of complement component C3. These findings reveal a non-canonical intracellular function of CFH in neurons. Together, our results identify CFH as a key mediator of neuronal resilience across the CNS in mice and humans and provide mechanistic insight into inflammatory neurodegeneration with implications for MS therapy and neuroprotection more broadly.
(© 2026. The Author(s).)
Competing Interests: Competing interests: The authors declare no competing interests.
References: Mol Cell. 2021 Jan 21;81(2):355-369.e10. (PMID: 33321093)
Ann Neurol. 2016 Jan;79(1):90-109. (PMID: 26505992)
Nature. 2026 Oct;658(8136):765-773. (PMID: 42686909)
Mol Ther Methods Clin Dev. 2017 Nov 10;9:1-11. (PMID: 29234687)
Sci Rep. 2017 Dec 4;7(1):16878. (PMID: 29203879)
Nat Chem. 2025 Dec;17(12):1963-1973. (PMID: 41006598)
Nat Cell Biol. 2025 Jun;27(6):902-917. (PMID: 40514428)
J Am Soc Nephrol. 2018 Jun;29(6):1649-1661. (PMID: 29588430)
Science. 2005 Apr 15;308(5720):421-4. (PMID: 15761121)
Nat Genet. 2000 Jun;25(2):139-40. (PMID: 10835623)
Blood. 2007 Sep 1;110(5):1516-8. (PMID: 17495132)
J Exp Med. 2021 May 3;218(5):. (PMID: 33661276)
Brain Behav Immun. 2020 Jul;87:739-750. (PMID: 32151684)
Proc Natl Acad Sci U S A. 2020 May 5;117(18):9942-9951. (PMID: 32321835)
Nat Rev Dis Primers. 2021 May 6;7(1):31. (PMID: 33958600)
Front Immunol. 2021 Dec 09;12:752916. (PMID: 34956184)
Science. 2005 Apr 15;308(5720):419-21. (PMID: 15761120)
Proc Natl Acad Sci U S A. 2018 Jan 9;115(2):E302-E309. (PMID: 29279367)
Lancet Neurol. 2023 Jan;22(1):78-88. (PMID: 36410373)
Cell. 2024 Jul 25;187(15):4043-4060.e30. (PMID: 38878778)
Nat Neurosci. 2019 Jun;22(6):887-896. (PMID: 31011226)
J Comp Neurol. 2014 Apr 15;522(6):1411-43. (PMID: 24318667)
J Neuroinflammation. 2022 Feb 23;19(1):54. (PMID: 35197067)
Nat Rev Mol Cell Biol. 2024 Jun;25(6):424-442. (PMID: 38366038)
Nat Chem Biol. 2020 Mar;16(3):302-309. (PMID: 32080622)
Immunol Rev. 2023 Jan;313(1):25-45. (PMID: 36382387)
Immunity. 2023 Aug 8;56(8):1809-1824.e10. (PMID: 37499656)
Signal Transduct Target Ther. 2021 Feb 3;6(1):49. (PMID: 33536413)
Neuron. 2019 Dec 18;104(6):1039-1055.e12. (PMID: 31784286)
Am J Med Genet B Neuropsychiatr Genet. 2008 Sep 5;147B(6):720-6. (PMID: 18163432)
Neuron. 2025 Feb 05;113(3):396-410.e9. (PMID: 39708806)
J Neuroimmunol. 1992 Jun;38(3):229-40. (PMID: 1376328)
OMICS. 2012 May;16(5):284-7. (PMID: 22455463)
Genome Biol. 2014;15(12):550. (PMID: 25516281)
Commun Biol. 2026 Mar 05;9(1):. (PMID: 41781748)
Nat Neurosci. 2024 Dec;27(12):2354-2365. (PMID: 39501036)
Nature. 2025 Jun;642(8067):492-500. (PMID: 40335696)
Nat Neurosci. 2017 Aug;20(8):1172-1179. (PMID: 28671695)
Nat Methods. 2017 Nov;14(11):1083-1086. (PMID: 28991892)
Nat Cell Biol. 2014 Dec;16(12):1180-91. (PMID: 25402683)
Nature. 2021 Sep;597(7878):709-714. (PMID: 34497421)
Nat Methods. 2023 Sep;20(9):1323-1335. (PMID: 37550580)
Science. 2019 Jan 25;363(6425):. (PMID: 30679343)
Lancet Neurol. 2022 Dec;21(12):1120-1134. (PMID: 36179757)
Nature. 2022 Aug;608(7924):778-783. (PMID: 35922516)
Glia. 2023 Mar;71(3):588-601. (PMID: 36377669)
Nat Rev Neurosci. 2024 Jul;25(7):493-513. (PMID: 38789516)
Nat Med. 2012 Dec;18(12):1805-11. (PMID: 23160238)
Nat Neurosci. 2025 Jun;28(6):1160-1173. (PMID: 40404995)
Cell. 2026 Jan 8;189(1):287-306.e35. (PMID: 41349546)
Nat Genet. 2026 Feb;58(2):418-433. (PMID: 41578023)
Nat Biotechnol. 2024 Feb;42(2):293-304. (PMID: 37231261)
Sci Adv. 2022 Aug 5;8(31):eabm5500. (PMID: 35930635)
Nucleic Acids Res. 2025 Jan 6;53(D1):D543-D553. (PMID: 39494541)
J Clin Invest. 2024 Jun 18;134(16):. (PMID: 39145444)
Nature. 2019 Sep;573(7772):75-82. (PMID: 31316211)
Nat Rev Immunol. 2024 Feb;24(2):118-141. (PMID: 37670180)
Immunity. 2020 Mar 17;52(3):513-527.e8. (PMID: 32187519)
Cell. 2025 Aug 21;188(17):4567-4585.e32. (PMID: 40532699)
JAMA Neurol. 2017 May 1;74(5):574-582. (PMID: 28135360)
Neurology. 1998 Mar;50(3):715-8. (PMID: 9521262)
N Engl J Med. 2018 Jan 11;378(2):169-180. (PMID: 29320652)
Cell Death Differ. 2023 Sep;30(9):2092-2103. (PMID: 37542104)
Sci Rep. 2020 Jun 17;10(1):9802. (PMID: 32555229)
Nature. 2011 Oct 05;478(7367):76-81. (PMID: 21979047)
Nature. 2023 Dec;624(7991):415-424. (PMID: 38092908)
F1000Res. 2021 Sep 28;10:979. (PMID: 35814628)
J Immunol. 2025 Sep 1;214(9):2150-2164. (PMID: 40356067)
Nat Biotechnol. 2018 Oct;36(9):880-887. (PMID: 30125270)
JAMA Neurol. 2018 Sep 1;75(9):1071-1079. (PMID: 29710121)
Nat Protoc. 2019 Jan;14(1):68-85. (PMID: 30464214)
Nat Commun. 2017 Jan 16;8:14049. (PMID: 28091601)
Nat Rev Neurosci. 2020 Jan;21(1):5-20. (PMID: 31780820)
Brain. 2010 Jun;133(Pt 6):1591-601. (PMID: 20410146)
Trends Immunol. 2013 Aug;34(8):410-22. (PMID: 23707039)
Nat Rev Immunol. 2022 Dec;22(12):734-750. (PMID: 35508809)
Cell Metab. 2008 Sep;8(3):237-48. (PMID: 18762024)
Brain. 1996 Jun;119 ( Pt 3):723-40. (PMID: 8673486)
Genome Med. 2011 Jan 18;3(1):3. (PMID: 21244703)
Substance Nomenclature: 80295-65-4 (Complement Factor H)
0 (CFH protein, human)
0 (Reactive Oxygen Species)
0 (Complement C3)
Entry Date(s): Date Created: 20260903 Date Completed: 20261015 Latest Revision: 20261017
Update Code: 20261017
PubMed Central ID: PMC13668678
DOI: 10.1038/s41586-026-10981-y
PMID: 42686909
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1476-4687
DOI:10.1038/s41586-026-10981-y