Targeting the excessive activation of immune cells called neutrophils, and the associated oxidative stress, may be a therapeutic strategy in patients with multiple sclerosis (MS), according to a mouse study.
The study, “Deficiency of Socs3 leads to brain-targeted EAE via enhanced neutrophil activation and ROS production,” was published in the journal JCI Insight.
Neutrophils are the most common type of white blood cells, and are the first responders to foreign antigens or inflammation. Accordingly, their levels increase in response to infections and injuries.
Neutrophils have been implicated in MS and other autoimmune diseases, but their precise role is not entirely clear.
Prior work in a severe mouse model of MS, called atypical experimental autoimmune encephalomyelitis (EAE), showed that disease processes are driven by neutrophils. These mice typically show damage in the cerebellum, a brain area with a major role in the control of motor coordination, balance, and speech.
Previous research also revealed that a cell signaling pathway known as JAK/STAT is dysregulated in MS and in the EAE model, and that an inflammatory molecule called the granulocyte colony-stimulating factor (G-CSF) — key for the maturation of neutrophils — is associated with disability, relapses, and lesion burden in MS patients.
Now, a team at the University of Alabama at Birmingham used the atypical EAE mouse model to study the role of neutrophils in MS.
For this purpose, the Socs3 gene in the mice was deleted, leading to an overly active STAT3 protein — one of the components of the JAK/STAT pathway — and neutrophil infiltration in the cerebellum. Exaggerated activation of STAT3 has been observed in immune cells from MS patients, and correlates with disease progression.
Results showed that these neutrophils were abnormally activated, and produced excessive levels of reactive oxygen species (ROS) — free radicals that may damage DNA, lipids (fat), and proteins. Researchers also found overactivation — as assessed via the expression of cell-surface markers — and greater oxidative stress in neutrophils in response to G-CSF.
Approaches that depleted either ROS or G-CSF delayed the onset and reduced the severity of atypical EAE, while also lowering neutrophil infiltration in the cerebellum at the peak of EAE. Depleting G-CSF also lessened the loss of the protective layer of nerve fibers, called myelin, which is typically destroyed in MS.
To assess the most altered signaling pathways and proteins in neutrophils lacking Socs3, the researchers subsequently analyzed their messenger RNA — produced from DNA in gene expression — after stimulation with G-CSF. More than 2,000 genes showed differential levels compared with neutrophils with Socs3, implicated in pathways such as those related to neutrophil activation and migration.
“These findings contribute to our understanding of the pathobiology of brain-targeted EAE, and document the detrimental role of neutrophils in autoimmune neuroinflammation,” Etty “Tika” Benveniste, PhD, and Hongwei Qin, PhD, the study’s senior authors, said in a press release.
The altered cellular signaling in neutrophils in this mouse model “may explain the detrimental role of [G-CSF] in [MS] patients,” the scientists wrote in the study. The results also suggest that “both [G-CSF] and neutrophils may be therapeutic targets in MS.”