Projects per year
Dysregulated release of neutrophil azurophilic granules causes increased tissue damage and amplified inflammation during autoimmune disease. Anti-neutrophil cytoplasmic antibodies (ANCA) are implicated in the pathogenesis of small vessel vasculitis and promote adhesion and exocytosis in neutrophils. ANCA activate specific signal transduction pathways in neutrophils that have the potential to be modulated therapeutically to prevent neutrophil activation by ANCA. We have investigated a role for diacylglycerol kinase (DGK) and its downstream product phosphatidic acid (PA) in ANCA induced neutrophil exocytosis. Neutrophils incubated with the DGK inhibitor R59022, prior to treatment with ANCA, exhibited a reduced capacity to release their azurophilic granules, demonstrated by a component release assay and flow cytometry. PA restored azurophilic granule release in DGK inhibited neutrophils. Confocal microscopy revealed that R59022 did not inhibit translocation of granules, indicating a role for DGK during the process of granule fusion at the plasma membrane. In investigating possible mechanisms by which PA promotes neutrophil exocytosis, we have demonstrated that exocytosis can only be restored in R59022 treated cells through simultaneous modulation of membrane fusion and increasing cytosolic calcium. PA and its associated pathways may represent viable drug targets to reduce tissue injury associated with ANCA associated vasculitic diseases and other neutrophilic inflammatory disorders.
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- 1 Finished
The role of neutrophil serine proteases in vasculitic glomerulonephritis and potential as therapeutic targets
1/06/07 → 30/11/11
Project: Research Councils