OLFM4 regulates the antimicrobial and DNA binding activity of neutrophil cationic proteins

Neutrophil cationic proteins (NCPs) are a group of granule antimicrobial and inflammatory proteins released by activated neutrophils. These proteins primarily function via their positively charged structure, which facilitates interactions with bacterial membranes and the formation of immunogenic DNA complexes, thereby contributing to the initiation of wound repair in injured skin. After analyzing the structural properties of secreted neutrophil granule proteins, we identified OLFM4 as the only negatively charged molecule that interferes with NCP oligomerization. Through this interference, OLFM4 can inhibit neutrophil-mediated bacterial killing and DNA complex-dependent activation of Toll-like receptor 9 (TLR9) in plasmacytoid dendritic cells (pDCs) and neutrophils. While addition of exogenous OLFM4 blocks these processes, OLFM4 inhibition enhances neutrophil-dependent bacterial killing and DNA complex formation, ultimately leading to accelerated closure of skin wounds.