Inflammation is a host response that evolved to counteract noxious stimuli that result from infection or tissue injury, and serves to return the affected tissue to homeostasis. Cell death-associated sterile inflammation is a major contributor to secondary tissue damage associated with multiple conditions such as myocardial infarction, transplantation, and stroke. Damaged tissues are thought to elicit their inflammatory effects through the sudden release from cells of endogenous Damage-Associated Molecular patterns (DAMPs) that serve to recruit and modulate the function of immune cells. In vertebrates, a diversity of molecules have been implicated as DAMPs, including ATP, uric acid, and F-actin.
In mammals, F-actin is recognised as a DAMP by the C-type lectin receptor DNGR1, expressed on CD8+ Dendritic cells (DCs), that signals to favour the cross-presentation of dead-cell antigen to CD8+ T-cells. Independently of its work on DNGR-1, the host laboratory discovered that extracellular actin elicits a JAK-STAT-dependent inflammatory response in the fruit fly (Drosophila melanogaster). DNGR-1 does not have a functional homolog in fly, therefore the actin sensor remains obscure. In order to identify the molecular sensor of extracellular actin we have conducted an in silico-based screen to identify a candidate list of potential sensors. To functionally evaluate these candidates, we will conduct in vivo RNAi and in vitro gain-of-function screens in Drosophila. We will validate the role for this novel sensor in mediating sensing of extracellular actin through multiple genetic and biochemical approaches. We expect our proposal to give novel insights into the signalling transduction and immunobiology of host responses to evolutionary conserved DAMPs. We anticipate that by understanding cytoskeletal-mediated innate inflammatory responses in fly, it will provide important insights into the evolution of similar damage sensor response pathways in higher organisms
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