Although the exact mechanisms of NETs formation are still poorly understood, some key steps have been identified, including reactive oxygen species (ROS) production mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase,[16] histone guanylation induced by peptidyl deiminase 4 (PAD4),[17] and chromatin deprotonation regulated by various proteases such as NE and MPO.[18] Despite intensive investigation, much remains unknown about mechanisms linking inflammation of the intestinal epithelium in IBD to NETs formation that occurs in IBD. This evidence concerns the gene ELANE and inflammatory bowel disease.