Peptidylarginine deiminase 4 deficiency improves elastase-induced formation of neutrophil extracellular traps and emphysema in mouse lung

Neutrophil extracellular traps (NETs) are associated with the extracellular release of nuclear chromatin decorated with cytoplasmic proteins. Excessive release of NETs has been reported in chronic lung diseases, including chronic obstructive pulmonary disease (COPD). However, the role of NETs in the pathogenesis of COPD remains unclear. Peptidylarginine deaminase 4 (PAD4) contributes to NET formation. Therefore, in an elastase (ELS)-induced emphysema mouse model, we examined the role of PAD4 using the Padi4 gene knockout (KO) mice. First, we confirmed that ELS induced NET formation in the lungs. Although PAD4 deficiency did not affect the cellular profile of bronchoalveolar lavage fluid (BALF), PAD4 deficiency suppressed ELS-induced neutrophil migration and NET expression in the parenchyma of the lung. Additionally, PAD4 deficiency ameliorated emphysema and apoptosis in lung cells. Finally, we examined the effects of PAD4 on comprehensive gene expression signatures using RNA sequencing. Enrichment analysis of the transcriptomic data revealed that the expression of several genes associated with COPD pathogenesis was altered in the KO mice. Overall, the results suggest that PAD4 deficiency improves NET formation and emphysema in the lungs; this pathway can be a potential therapeutic target for the treatment of COPD. To examine the inhibitory effect of PAD4 on the formation of NETs and emphysema, we used PAD4-knockout (PAD4-KO) mice. ELS was administered intratracheally to wild-type (Wt) and PAD4-KO mice to create a model of emphysema. The control group was administered PBS. On days 1 and 14, bronchoalveolar lavage fluid (BALF) and lung tissue were examined histopathologically, and whole lung RNA sequencing was performed.