Granulocyte macrophage colony stimulating factor and macrophage colony stimulating factor compete to differentially regulate bone marrow-derived macrophage activation and polarization
Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) and Macrophage Colony Stimulating Factor (M-CSF) are two highly regulated cytokines with a variety of roles in the immune system. One of their most impactful roles is in influencing the proliferation, differentiation, and polarization of macrophages. These cytokines have been implicated in a variety of diseases ranging from autoimmune diseases such as lupus to inflammatory diseases like atherosclerosis or even viral infections like HIV. The CSFs can be used to differentiate murine macrophages in vitro, however the differences between these two types of macrophages have not been extensively studied, especially in the area of viral infection. Additionally, the nature of GM-CSF and M-CSF’s competing effects when administered to macrophages simultaneously has not been well defined. This work explores the differences between M-CSF and GM-CSF derived bone marrow macrophages in terms of innate immune signaling via TLR activation and cytokine production after infection with lymphocytic choriomeningitis virus (LCMV), a well-defined model of viral infection in mice. My results show that LCMV is capable of modulating phosphorylation of TLR associated signaling proteins in different ways between these two cell types, and that LCMV blocks further phosphorylation of these proteins by the TLR7 ligand resiquimod (R848). This work also shows the effects of mixing differing proportions of GM-CSF and M-CSF and administering them to macrophages differentiated using one CSF or the other, along with the effects of differentiating macrophages from bone marrow under these different CSF proportions. The data indicated that GM-CSF holds a partial dominance over the polarization of macrophages to produce certain proinflammatory cytokines and a strong dominance in governing macrophage morphology. This thesis contributes to the overall understanding of these two important cytokines, their differing influences on macrophage polarization, and how they can be used to modulate macrophage cytokine production and response to viral infection, potentially informing future study of these cytokines as treatments or targets for treatment in diseases where macrophages have been implicated.
URI for this recordhttp://hdl.handle.net/1974/26457
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