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Shared and unique mechanisms of macrophage-like neutrophils in EAE

Hawkins, W;Ryder, F;

Autoimmune demyelinating diseases (ADDs) are a leading cause of neurological disability in youth and adults, especially in Canada; the best-known of which is multiple sclerosis (MS); others include neuromyelitis optica spectrum disorder. These diseases are characterized by destruction of myelin and loss of nerve conductivity leading to motor deficits and deteriorating quality of life. ADDs have been studied for nearly two centuries and disease-mitigating therapies are now available for patients; however, a cure has not yet been found. Demyelination proceeds largely via the reaction of autospecific T cells with endogenous myelin proteins, in cooperation with B cells, macrophages and dendritic cells; the root cause of this autoreactivity is still unknown. Yet it is becoming increasingly clear from the study of animal models of MS that depletion of neutrophils, an abundant innate leukocyte population, has the potential to block the development of disease symptoms. We therefore aim to comprehend the molecular reasons behind this phenomenon in mice and translate our findings to the human case. This work aims, firstly, to summarize the facts known about neutrophils in MS, neuromyelitis optica, and other ADDs, as well as in mouse models of demyelination; secondly, to present the results of experiments on neutrophils with the model system experimental autoimmune encephalomyelitis (EAE). We have found that neutrophils in EAE that migrate to the central nervous system undergo transcriptional and proteomic changes that leave them in a putatively activated state. These activated neutrophils physically interact with T and B lymphocytes in the inflamed spinal cord. Furthermore, we use an improved model of EAE, that better describes MS, to show that neutrophils act through the novel gene Asprv1 to prolong and worsen inflammation. This study sheds light on the subtleties of neutrophils in a societally relevant context and provides data for the continued investigation into neutrophil biochemistry and systems biology