Study: Mouse gene deletion offers clues to MS pathogenesis

May 29, 2019
A new study suggests how dysregulated neutrophils cause damage in a severe mouse model form of multiple sclerosis called atypical EAE, which attacks cerebellum brain tissue.

Neutrophils are the most common white blood cells in the body, but their exact function in MS is unclear. Their normal, healthy function is to protect humans, as neutrophils speed to sites of infection or inflammation, aided by their ability to crawl out of the bloodstream and into affected tissues.

Researchers at the University of Alabama at Birmingham artificially dysregulated the JAK/STAT signaling system by using mice with a deleted Socs3 gene. In the absence of Socs3, the JAK/STAT pathway is overly active and promotes inflammation. As a result, mice with Socs3 deletion have a severe, brain-targeted, atypical form of EAE that is linked to cerebellar neutrophil infiltration and overactivation of STAT3, one of the seven STAT proteins that function in the JAK/STAT cell signaling pathway.

The researchers found that neutrophils from the cerebellum of mice lacking Socs3 showed a hyperactivated phenotype and produced excessive amounts of reactive oxygen species, chemically active compounds that can damage cell structures. However, if mice were given treatments to neutralize the reactive oxygen species, the onset of the disease was delayed and disease severity was reduced.

The mechanisms causing these changes were an enhanced STAT3 activation in Socs3-deficient neutrophils, a hyperactivated phenotype in response to granulocyte colony-stimulating factor, and an increased production of reactive oxygen species after neutrophil priming by granulocyte colony-stimulating factor. Furthermore, when compounds were given to mice to neutralize granulocyte colony-stimulating factor, the incidence and severity of atypical EAE was significantly reduced.

Results of mouse model studies sometimes do not translate to humans and may be years away from being a marketable treatment.

The findings were published in the journal JCI Insight.

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