Necroptosis Drives Netosis and ANCA-Associated Vasculitis Save

PNAS reports that ANCA induced neutrophil activation, generation of neutrophil extracellular traps (NETS), and vasculitis are regulated by necroptosis. Using inhibitors of necroptosis-inducing kinases they were able to prevent ANCA associated vasculitis (AAV) in animal models. 

ANCA activates neutrophils and activated neutrophils damage the endothelium, leading to vascular inflammation and necrosis. Previously the signaling pathways by which ANCA induces NETs nor the potential mechanism(s) by which NETs affect the endothelium were unclear.

Investigators showed that ANCA induces NETs via receptor-interacting protein kinase (RIPK) 1/3- and mixed-lineage kinase domain-like (MLKL)- both being key mediators of the necroptosis pathway. They used pharmacologic and genetic approaches in murine disease models and provided AAV patient data supporting the concept that necroptosis and NET formation are relevant in causing anti-MPO antibody-mediated ecrotizing crescentic glomerulonephritis.

These studies identified a mechanistic link between ANCA-induced neutrophil activation, necroptosis, NETs, activation of the alternate pathway and subsequent endothelial damage. Such findings pave the way fo rspecific necroptosis inhibitors to be evaluated in clinical studies as a novel therapeutic strategy for AAV.