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-? 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.
GM-CSF, a proinflammatory mediator, is considered essential for the development of experimental autoimmune encephalomyelitis, an animal model of human multiple sclerosis. This project aims to study its pathogenesis in depth and to develop an effective and specific way to block this molecule, thus making it a novel therapy for human autoimmune disease.
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