Role of cGAS and STING in perpetuating inflammation in vasculitis

Neutrophil Extracellular Traps (NETs) are a form of regulated cell death to enhance host protection against infection. However, they also have the potential to cause harm by releasing injurious enzymes that cause direct damage to endothelial cells and surrounding tissue. A large component of NET is a DNA backbone, which is phagocytosed by macrophages and other myeloid cells. Once engulfed into phagosomes, immune sensor cyclic GMP-AMP synthase (cGAS) and induced type 1 IFN production is induced, and inflammation is perpetuated. NETs play a major role in the induction of an autoimmune disease where the small blood vessels of the glomerulus become inflamed. This disease termed anti neutrophil cytoplasmic antibody vasculitis (AAV), can lead to renal failure, and if left untreated death. Current treatment is toxic and patients are left severely immunocompromised. This project will examine the interaction between NETs and cGAS, with aim to find more targeted therapies for this disease. Animal models of AAV, and human kidney biopsies will be used to explore the different interactions. Techniques used will be: FACS, confocal microscopy, super resolution microscopy, immunohistochemistry, RT-PCR, ELISAS, cytometric bead assays, and cell culture.