The signalling networks regulating pro-and anti-inflammatory responses are poorly understood. Here, a hypothesis is proposed that these responses have signalling state counterparts at the level of individual membranes. To address this, defined bacterial pr o-and anti-inflammatory ligands will be coated onto beads. During phagocytic uptake of such beads by macrophage plasma membrane, receptors are selected and enriched in phagosomes, which are isolated, offering a dynamic and accessible membrane-system. This model system will be used to decipher membrane-signalling signatures of specific pro- and anti-inflammatory receptors, both in-vitro and in cells.
The host group showed that activation of actin assembly at the phagosomal membrane, mostly by pro-anti-inflammatory lipids, directly correlated with subsequent fusion with lysosomes and pathogen killing. Using different candidate effectors, mostly lipids, I will address how these membrane- signalling networks regulate these functions for the two types of phagosomes. The results from this study will be combined with bio-informatic approaches by collaborators that have allowed predictions for key signalling pathways operating in the phagosomal membrane.
The predictions gained will be tested and used to refine the theoretical modelling. Complementary analysis in macrophages will follow the cellular response to the beads, addressing key molecules in inflammatory-anti-inflammatory signalling, like NfkappaB and interleukin synthesis, and phago-lysosome fusion. The project has medical relevance by allowing manipulation of phagosomal signalling towards pathogen killing, and identifying medically relevant anti-inflammatory lipids.
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