Inhibition of netosis with PAD inhibitor attenuates endotoxin shock induced systemic inflammation

Neutrophils play a pivotal role in innate immunity and participate in a range of immunological disorders. Excessive neutrophil extracellular traps formed at infection and tissue damage sites are detrimental to the local tissue and further exacerbate inflammation. Protein arginine deiminases mediate histone citrullination and NET formation thereby regulating endotoxin shock response. However, the molecular mechanisms are less known. Here we report that inhibition of netosis attenuates inflammation in a LPS induced lethal endotoxic shock model in mice. Albeit a higher number of neutrophils are accumulated in peritoneal cavity the primary inflammatory site, the level of inflammatory signals is greatly reduced after netosis inhibition with a PAD inhibitor. In lungs under endotoxic stress, gene expression analyses indicate that LPS induced a drastic increase in inflammatory gene expression. In contrast, lung tissue damage and inflammation were much reduced after PAD inhibition to reduce netosis. In summary, we found NET formation inhibition as a new avenue to manage inflammatory damages under endotoxic stress. Overall design: We performed gene expression profiling analysis using data obtained from RNA-seq of 3 different treatment groups of mice lung tissue: control group with 3 samples, LPS group with 3 samples, and dual treatment group with PAD4 inhibitor pretreated and LPS with 2 samples.