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UKE Paper of the Month September 2026

Intracellular complement factor H protects neurons during CNS inflammation

Christina Mayer, Marcel S. Woo, Jana K. Sonner, Lars Binkle-Ladisch, Felix Fischbach, Patricia Sekol, Matthew D. Smith, Fernando Lucas-Ruiz, Darwin Manteufel, Kuno M.-J. Mattern, Lena Kristina Pfeffer, Yubing Guo, Bente Siebels, Albert Miguela, Vanessa Vieira, Nina Meurs, Simone Bauer, Sophia Schwarz, Sonia Wulf, Anne Katrin Mühlig, Jan Broder Engler, Marcus Conrad, Florence M. Bareyre, Thorsten Wiech, Susanne Krasemann, Markus Glatzel, Peter F. Zipfel, Tilo Freiwald, Peter A. Calabresi, Lucas Schirmer, Manuel A. Friese

ABSTRACT:
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.

STATEMENT
“This study reveals a previously unknown, complement-independent intracellular function of complement factor H as a neuron-intrinsic protector against inflammatory and oxidative injury. It bridges human single-nucleus transcriptomics, mechanistic cell biology and in vivo neuroimmunology, progressing from the identification of resilient neuronal subtypes to therapeutic proof-of-concept in experimental CNS inflammation. The work establishes a new concept of neuronal resilience with implications for progressive MS and neuroprotection more broadly. It also exemplifies highly interdisciplinary research at UKE, integrating neuroimmunology, translational immunology, internal medicine, proteomics, pathology and neuropathology through national and international collaborations“

BACKGROUND:
The study was led by Prof. Manuel A. Friese at the INIMS, with co-first authors Dr. Christina Mayer and Dr. Marcel S. Woo. Their work focuses on mechanisms of inflammatory neurodegeneration and neuron-intrinsic resilience in MS. UKE co-authors contributed expertise from HCTI, Internal Medicine III/HCKH, Mass Spectrometry and Proteomics, Pathology/Nephropathology and Neuropathology. Partners in Mannheim/Heidelberg, Johns Hopkins, Munich, Jena, Murcia and Girona added complementary expertise. Funding included DFG, NMSS, NIH, ERC, BMBF, the UKE Clinician-Scientist Program and Else Kröner-Fresenius-Stiftung.

Nature, 2026; DOI: 10.1038/s41586-026-10981-y

Congratulations to all authors!

Next PoM: To apply, the publication must have been published in September 2026. Applications will be considered in two rounds of the selection process, i.e. two months. Please send your completed PoM application to Dr. Anne Wulf by 31/10/2026