Pad4fl/fl floxed mice possess loxP sites flanking exons 9-10 of the peptidyl arginine deiminase, type IV (Padi4) gene. These exons contain part of the PAD4 active site, as well as four additional residues that are essential for Ca2+ binding. PAD4 is an enzyme responsible for the citrullination and deimination conversion of arginine to citrulline residues on histones. PAD4-mediated deimination of histone H3 and H4 is required for the formation of neutrophil extracellular traps (NETs), specialized anti-microbial structures comprised of decondensed chromatin decorated with microbicidal agents. NETs are responsible for killing gram-positive and gram-negative bacteria as well as fungi. Increased amounts of NETs are detrimental in chronic neutrophil-mediated inflammation such as the lung diseases chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) due to increased severity of lung obstruction. Homozygous mice are viable and fertile. When bred to mice that express tissue-specific Cre recombinase, resulting offspring will have exons 9-10 deleted in the cre-expressing tissues.
When bred to B6.C-Tg(CMV-cre)1Cgn/J mice (Stock No. 006054) with widespread Cre recombinase expression, histone deimination is absent in neutrophils of resulting offspring, and they are defective in NET formation. PAD4 KO mice lose significantly more weight during influenza A infection, but retain normal survival. The number of lung infiltrating leukocytes was similar to that seen in wildtype mice during infection.
