Intracellular complement factor H protected neurons during CNS inflammation

In cell and mouse experiments, factor H protected neurons from inflammatory damage

On September 2, Nature published a study of factor H, a protein that usually acts outside cells as a regulator of the innate immune system. In human postmortem tissue, the CFH gene, which encodes this protein, was more active in neurons that were more resistant to damage. The authors used cell cultures and mice to examine how factor H acts inside neurons. Its SCR20 domain provided protection by reducing oxidative damage to cell membranes.

Retinal ganglion cells are neurons whose axons form the optic nerve. The authors isolated their nuclei from the maculae of ten donors with multiple sclerosis and ten control donors. After quality control, the analysis included 105 502 gene expression profiles. In these samples, the cell subtypes that were relatively more abundant in multiple sclerosis had higher CFH expression.

The authors tested the role of CFH in a mouse model of autoimmune inflammation in the central nervous system. They inactivated Cfh, the gene encoding factor H, in neurons. These mice developed more severe disease, greater neuronal loss and axonal damage, and lower visual acuity and contrast sensitivity.

The amount of factor H in neurons increased during inflammatory and oxidative stress. The protein accumulated mainly in the endoplasmic reticulum, the intracellular network in which cells synthesize and process proteins. In cell experiments, CFH reduced levels of reactive oxygen species, which damage cells, and reduced lipid peroxidation, which damages membranes.

The authors introduced different forms of factor H into neurons. Forms containing the terminal SCR20 domain provided protection. The shortened mHDM-FH form, which remained inside the cell, retained this effect. When the culture medium was exchanged, protection persisted in cells that produced CFH themselves. In mice lacking C3, the gene encoding one of the complement proteins, neuronal mHDM-FH also reduced inflammation severity, neuronal loss, and axonal damage while preserving vision.

In two models of autoimmune CNS inflammation, mHDM-FH, its intracellular form, and SCR20 reduced neuronal loss and axonal damage. In the C57BL/6 model, the authors also measured visual function and found that it was preserved.