Neutrophil extracellular traps in experimental autoimmune encephalomyelitis




Pratt, Gilbert Andrew, III

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Neutrophils play a vital role in innate immune defenses as first responders to perturbations in tissue homeostasis such as infection or physical injury. As a mechanism of defense, neutrophils undergo a novel cell death pathway called NETosis which results in the death of the cell and the release of extracellular traps (NETs); a method to sequester invading pathogens and the resulting inflammatory signals. This sequestration allows the pathogens to be centralized and destroyed by constitutive proteases and reactive oxygen species within the NETs scaffolding and cleared by macrophage. Aberrant release of NETs has been implicated in autoimmune diseases such as systemic lupus erythematosus, small vessel vasculitis, and rheumatoid arthritis. Neutrophils have been shown to be mediators of tissue damage in experiment autoimmune encephalomyelitis (EAE) the mouse model for the autoimmune disease multiple sclerosis (MS), but the mechanism of their indiscriminant histotoxicity is not completely defined. Recent studies suggested that proteases found within NETs can cause epithelial cell injury which could contribute to the formation of brain lesions in MS patients and EAE mice. Our studies show that the blockade of interferon gamma (IFN-γ) results in significant increase of clinical disease score and infiltrating neutrophils in the brain at day 21 of EAE disease. With the blockade of IFN-γ, we found a significant increase of NETs in the brains of EAE diseased mice and demonstrated that NETs released in EAE is not dependent upon IFN-γ signaling. Further elucidation of the initiating mechanism of NETosis or key components in its molecular pathway could represent a novel target for drug therapies.


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EAE, IFN-γ, Interferon gamma, Multiple Sclerosis, NETs, Neutrophil



Integrative Biology