Regulation of SNARE proteins in macrophages by colony stimulating factor-1

Deposited with permission of the author. © 2007 Adrian Achuthan.Macrophages serve key roles in host defence by initiating inflammatory responses to infection and/or injury. They contribute to innate immunity by secreting a range of pro-inflammatory cytokines (e.g. TNF and IL-6) upon activation as well as by phagocytosing pathogens and dead cells, which is necessary for the resolution of inflammation and effective wound repair. Macrophages also contribute to adaptive immunity by functioning as antigen presenting cells.Colony stimulating factor 1 (CSF-1) is the major growth factor governing the differentiation, proliferation and survival of macrophages. Although not as well appreciated, CSF-1 also regulates some of the immune functions of macrophages, such as cytokine secretion and phagocytosis. However, the mechanisms by which CSF-1 governs the immune functions of macrophages are poorly understood. Cytokine secretion, phagocytosis and antigen presentation involve various vesicle trafficking and membrane fusion events, processes in which SNARE proteins play vital roles. Thus, the hypothesis tested in this thesis was that CSF-1 modulates the immune functions of macrophages by regulating the expression and/or activity of SNARE proteins that regulate endocytic and exocytic processes.In this study, the endosomal SNARE protein syntaxin 7 was identified, via microarray analysis, as a CSF-1 inducible gene in primary mouse macrophages. Syntaxin 7 has previously been detected in phagosomal membranes in macrophages. Furthermore, syntaxin 7 has recently been implicated in the secretion of cytokines (e.g. TNF) from macrophages by forming a novel complex with syntaxin 6, Vti1b and VAMP3