Intracellular complement factor H protects neurons during CNS inflammation

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 an unexpected neuroprotective role for intracellular complement factor H (CFH) in neurons. Using single-nucleus RNA sequencing of RGCs from MS donors and controls, we found that CFH expression strongly correlated with intrinsic resilience to RGC degeneration. Mechanistically, CFH was induced in neurons in the retina and other CNS regions in response to inflammatory and oxidative stress, where it limited the accumulation of reactive oxygen species and lipid peroxidation. CFH localised to the endoplasmic reticulum, a major site of lipid peroxidation during neuronal ferroptosis. Its protective activity depended on the C-terminal SCR20 domain and was independent of CFH secretion, remaining preserved in the absence of complement component C3. These findings reveal a previously unrecognised, 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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Bente Siebels  

LAB HEAD: Dr. Bente Siebels

PROVIDER: PXD080433 | Pride | 2026-10-26

REPOSITORIES: Pride