Ahrens, S; (2014) Extracellular actin in innate immunity. Doctoral thesis , UCL (University College London).

Abstract

The innate immune system is capable of responding to tissue injury by detecting the abnormal exposure of intracellular, often ubiquitously expressed, molecules referred to as damage-associated molecular patterns (DAMPs). DAMPs are normally sequestered inside healthy cells but become exposed to the extracellular environment upon loss of membrane integrity during cell death. Exposed DAMPs are then recognised by receptors of the innate immune system. One such DAMP receptor is DNGR-1 (CLEC9A), which is expressed on CD8+ DCs, a rare but specialised subset of DCs involved in regulating T cell responses. Loss of DNGR-1 on CD8+ DCs impairs cross-presentation of dead-cell associated antigens to CD8+ T-cells indicating that DNGR-1 couples DAMP recognition to the generation of cytotoxic T cell immune responses. Prior to the work presented in this thesis, the DAMP ligand for DNGR-1 had not been identified. Using a variety of experimental approaches, I demonstrated that this ligand corresponds to filamentous actin (F-actin), a component of the cytoskeleton of all cells. Given its extreme evolutionary conservation, abundance and ubiquitous expression, as well as its association with tissue damage in a range of inflammatory conditions, actin possesses ideal DAMP characteristics. Thus, I further hypothesised that actin may engage receptors other than DNGR-1 and act as a universal and evolutionarily ancient sign of cell damage that is more generally detected by metazoans as a means of inducing sterile inflammation and/or tissue repair. In order to test this hypothesis, I made use of the Drosophila melanogaster model system. I found that actin injection into flies stimulates strong activation of the stress-induced JAK/STAT pathway without triggering immune defence pathways. Given the conservation of innate defence mechanisms in invertebrates and vertebrates, it is tempting to speculate that understanding the recognition of actin in Drosophila melanogaster will provide useful insights into the induction of inflammation in mammals.

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