PADI4 minor haplotype as risk factor for excessive NET formation and associated wound healing disorders in diabetes mellitus

Diabetes mellitus (DM) complicates wound healing, partly due to excessive neutrophil extracellular trap (NET) formation, a process regulated by the enzyme peptidyl-arginine deiminase 4 (PADI4). Circulating NET markers can predict the healing outcome of chronic wounds, but may not allow enough time for intervention as the accumulated NETs may have already damaged the tissue. In search for an early detectable risk marker, this study aimed at relating PADI4 haplotype, to PADI4 expression, NET formation and clinical outcomes, i.a. infections, delayed wound and bone healing, in 687 surgical patients (44.7% with DM). Pre-surgical PADI4 expression was 9.4-fold higher in patients with DM, especially those with complicated wound healing. The study linked PADI4 haplotypes to NET formation and clinical outcomes, finding that neutrophils with the PADI4 minor haplotype had higher PADI4 mRNA and protein levels and more rapidly produced a larger amount of NETs than neutrophils with the PADI4 major haplotype. Patients with DM and the PADI4 minor haplotype experienced the highest rates of delayed wound healing and infections. Our findings suggest that the PADI4 haplotype influences neutrophil behavior and clinical outcomes, making it a potential biomarker to screen patients with DM for their risk of developing wound healing complications. Graphical Abstract