Indolicidin attenuates sepsis inflammation and microbial burden by modulating TLR4 signaling pathway

Sepsis is a life-threatening condition characterized by a dysregulated host inflammatory response to infection, leading to high mortality rates globally. Current antibiotic treatments for sepsis-associated infections are often limited by antimicrobial resistance and their inability to effectively control the excessive inflammatory cascade. Indolicidin, a bovine-derived antimicrobial peptide, possesses both antimicrobial and immunomodulatory properties, making it a promising candidate for addressing the dual challenge of infection and inflammation in sepsis.

Researchers investigated indolicidin's protective effects and mechanisms in bacterial and fungal sepsis models. In vitro, they assessed biocompatibility. In vivo, murine models of Escherichia coli- and Candida albicans-induced sepsis were used to evaluate survival and microbial burden in kidneys. For mechanistic insights, RAW264.7 macrophages stimulated with lipopolysaccharide (LPS) were treated with indolicidin, assessing M1 polarization, reactive oxygen species production, and proinflammatory cytokine expression. Transcriptomic analyses were performed on macrophages and infected kidney tissues.

Indolicidin demonstrated good biocompatibility both in vitro and in vivo. In murine sepsis models, indolicidin significantly improved survival and reduced microbial burden in the kidneys. In LPS-stimulated RAW264.7 macrophages, indolicidin suppressed M1 polarization, reactive oxygen species production, and proinflammatory cytokine expression. Transcriptomic analyses consistently revealed that indolicidin 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.

This indicates a direct modulation of the TLR4 signaling pathway, which is crucial for sensing bacterial components and initiating inflammatory responses in sepsis.