Immunomodulatory effects of synthetic antimicrobial peptides on LPS-induced inflammatory responses in THP-1 macrophages

Macrophage polarization is critical for maintaining health and for recognizing and eliminating a diverse array of antigens. These disparate roles require distinct macrophage responses, and the induction of inappropriate macrophage responses is intimately associated with disease. It is therefore important to understand how macrophages respond to new biomedicines and to harness those with immune modulatory properties for therapeutic use. This study defines the effects of rationally designed antimicrobial peptides (AMPs) on macrophage polarization and function, compared with natural host-defense peptides (natural AMP LL-37 and antibiotic polymyxin B). Using an in vitro model system, our results show that the designed AMPs suppress pro-inflammatory cytokine production while enhancing anti-inflammatory responses, with potency comparable to LL-37, and mitigate the impact of LPS-induced inflammation. Furthermore, AMPs influence key molecular pathways, such as IRF3/IRF4 and PPAR-γ, favoring M2 polarization. These results highlight the amphiphilic, sequence-engineered design of the peptides, which enables controlled membrane interaction, low cytotoxicity, and structural adaptability, properties central to next-generation immune-active biomaterials. By coupling antimicrobial function with immune reprogramming, these synthetic AMPs act as dual-function agents capable of alleviating inflammatory conditions such as cytokine storm and promoting reparative macrophage phenotypes. This work identifies a new design framework for bioinspired, immunomodulatory peptide materials with potential applications in infection control, inflammatory disease management, and wound healing.