Mechanisms of GM-CSF effect in CNS autoimmune demyelination

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pro-inflammatory cytokine essential for the development and progression of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Although GM-CSF is mainly produced by pathogenic Th17 and Th1 cells, GM-CSF receptor (GM-CSFR) is not expressed on T and B cells, but is expressed on antigen-presenting cells (APCs). Among them, Ly6ChiCCR2+ monocytes are essential for the pathogenic role of GM-CSF in EAE. Further, GM- CSF signaling in peripheral, but not CNS cells, plays a vital role in the development of acute EAE. However, whether lack of GM-CSF signaling results in development of immunoregulatory APCs has not been studied, and the role of GM-CSF signaling in CNS cells in EAE chronicity, for which microglia activation plays a major role, remains unknown. Our preliminary results for the first time show enhanced production of immunoregulatory molecules in APCs, and increased IL-10 and Foxp3 expression in CD4+ T cells of mice lacking GM-CSF. Similarly, neutralizing GM-CSF in human monocyte culture results in an increase of IL-27 and TGF-β production. Based on these observations, we hypothesize that GM-CSF induces proinflammatory monocytes, whereas its blockade results in the induction of immunoregulatory APCs and suppression of EAE. We will test this hypothesis in the following specific aims: 1) To determine the impact of GM-CSF on phenotype of APCs and T cells in EAE. We will test the hypothesis that blockade of GM-CSF signaling in monocytes leads to the development of immunoregulatory APCs that promote development of Tr1/Treg cells, resulting in suppression of EAE. 2) To investigate the effect of GM-CSF on the phenotype of microglia/macrophages in chronic phase of EAE. We will test our hypothesis that GM-CSF promotes activation and pro-inflammatory M1 phenotype of macrophages/microglia in chronic phase of EAE, which contributes to disease chronicity. 3) To determine the effects of blocking GM-CSF on phenotype and function of human monocytes. We will test the hypothesis that GM-CSF promotes development of a proinflammatory phenotype of human monocytes. These studies should fill the gap in our knowledge on mechanisms of proinflammatory action of GM- CSF and its relevant cellular targets in EAE/MS, with potential therapeutic effect in certain autoimmune diseases.