Antineutrophil cytoplasm antibody-stimulated neutrophil adhesion depends on diacylglycerol kinase-catalyzed phosphatidic acid formation.
Patients with certain forms of systematic vasculitis, such as Wegener's granulomatosis, have circulating antineutrophil cytoplasmic antibodies (ANCA). These inappropriately stimulate circulating neutrophils adhere to and thereby obstruct small vessels. This, together with ANCA-induced degranulation and an oxidative burst, leads to local tissue damage. The signaling pathways that are activated by ANCA IgG are distinct from those that are involved in normal neutrophil activation. This study shows that diacylglycerol kinase is selectively activated by ANCA and that the generated phosphatidic acid is responsible for promoting neutrophil adhesion, in part through integrin activation. The data presented point to diacylglycerol kinase alpha as a novel but selective target for the development of drugs to treat this potentially fatal disorder.
Williams
Julie M
JM
CR-UK Institute for Cancer Studies, Birmingham University, Birmingham B15 2TT, UK.
Pettitt
Trevor R
TR
Powell
Wendy
W
Grove
Joseph
J
Savage
Caroline O S
CO
Wakelam
Michael J O
MJ
D019268:Antibodies, Antineutrophil Cytoplasmic / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002384:Catalysis; D002448:Cell Adhesion; D002867:Chromones / Q000494:pharmacology; D019852:Diacylglycerol Kinase / Q000502:physiology*; D006801:Humans; D007074:Immunoglobulin G / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology*; D010712:Phosphatidic Acids / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051966:Phospholipase C gamma / Q000502:physiology; D015398:Signal Transduction
D019268:Antibodies, Antineutrophil Cytoplasmic; D002867:Chromones; D007074:Immunoglobulin G; D009025:Morpholines; D010712:Phosphatidic Acids; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D019852:Diacylglycerol Kinase; D051966:Phospholipase C gamma; D002118:Calcium