Disulfiram inhibits neutrophil extracellular traps and attenuates inflammation in autoimmune experimental myeloperoxidase anti-neutrophil cytoplasmic antibody-associated vasculitis 2780

Abstract Description Myeloperoxidase anti-neutrophil cytoplasmic antibody-associated vasculitis (MPO-AAV) is characterized by inflammation of the small blood vessels of the kidney which develops into glomerulonephritis. Neutrophil extracellular trap (NETs) are implicated in the pathogenesis of MPO-AAV. However, no current treatments specifically target NETosis, an essential driver of disease progression. Gasdermin D (GSDMD) is a key mediator of NETosis, making it a promising therapeutic target. We investigated the therapeutic potential of Disulfiram (DSL) which inhibits GSDMD using in vitro NET assays and an in vivo experimental model of MPO-AAV that replicates the human disease. In vitro, DSL significantly reduced the production of neutrophils forming NETs, regardless of stimuli (LPS, TNFα, ionomycin, or C5a). In vivo, in the animal model mice treated with DSL had a significant reduction in kidney injury, infiltrating glomerular neutrophils, macrophages and CD4 T cells. DSL significantly reduced the number of NETs observed within kidney glomeruli compared to the vehicle control treatment group. DSL limited autoimmunity to MPO and targeted downstream inflammation via the inhibition of NETs, which prevented deposition of MPO to serve as an autoantigen perpetuating inflammation. These findings suggest that DSL disrupts innate immunopathological mechanisms, offering a novel approach to reducing inflammation and attenuating glomerulonephritis in AAV. Funding Sources National Health and Medical Research Council (NHMRC) Ideas grant 2001325 Topic Categories Therapeutic Approaches to Autoimmunity (THER)