Indolicidin Attenuates Inflammation by Modulating the TLR4 Signaling Pathway during Sepsis Progression

Sepsis is characterized by dysregulated inflammatory responses triggered by pathogen-associated molecular patterns (PAMPs) and remains a major cause of mortality worldwide. Although antibiotics are widely used for the treatment of sepsis-associated infections, their clinical efficacy is often limited by antimicrobial resistance and the inability to control excessive inflammatory responses. Indolicidin is a bovine-derived antimicrobial peptide with antimicrobial and immunomodulatory activities; however, its anti-inflammatory mechanisms in sepsis remain unclear. In this study, we investigated the protective effects and mechanisms of indolicidin in bacterial and fungal sepsis models. The results showed that indolicidin exhibited good biocompatibility both in vitro and in vivo. In murine models of Escherichia coli - and Candida albicans -induced sepsis, indolicidin significantly improved survival and reduced microbial burden in the kidneys. In RAW264.7 macrophages stimulated with lipopolysaccharide (LPS), a major PAMP of E. coli, indolicidin suppressed M1 polarization, reactive oxygen species production, and proinflammatory cytokine expression. Transcriptomic analyses of macrophages and infected kidney tissues revealed that indolicidin consistently downregulated inflammation-related pathways, chemokine signaling, and LPS-response pathways, including genes associated with IL-6, chemokines, and M1 macrophage markers such as CD80 and CD86. Mechanistically, indolicidin directly bound LPS, interacted with lipopolysaccharide-binding protein (LBP), and reduced the surface expression of CD14 and the TLR4/MD2 complex, indicating modulation of the TLR4 signaling pathway. Overall, this study highlights indolicidin as a dual-function peptide with antimicrobial and immunomodulatory activity and supports its potential as a therapeutic candidate against sepsis.