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

Zhishang Shi1, Yanting Wang1, Yijun Gu1

  • 1National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, College of Life Sciences, Nankai University, Tianjin 300071, China.

ACS Infectious Diseases
|June 17, 2026
PubMed

Insights

Indolicidin, a bovine peptide, shows promise for sepsis treatment by fighting infections and reducing harmful inflammation. It effectively improves survival rates and modulates immune responses in sepsis models.

Area of Science:

  • Immunology
  • Microbiology
  • Pharmacology

Background:

  • Sepsis is a life-threatening condition with high mortality, often inadequately treated by antibiotics due to resistance and uncontrolled inflammation.
  • Antimicrobial peptides (AMPs) like indolicidin possess both antimicrobial and immunomodulatory properties, but their specific anti-inflammatory roles in sepsis require elucidation.

Purpose of the Study:

  • To investigate the protective effects and underlying mechanisms of indolicidin in bacterial and fungal sepsis models.
  • To assess indolicidin's biocompatibility and its impact on inflammatory pathways and microbial burden.

Main Methods:

  • Sepsis models were established using *Escherichia coli* and *Candida albicans* in mice.
  • RAW264.7 macrophages were stimulated with lipopolysaccharide (LPS) to evaluate indolicidin's effects on M1 polarization, reactive oxygen species (ROS), and cytokine production.
  • Transcriptomic analysis was performed on macrophages and kidney tissues.
  • Mechanistic studies involved assessing indolicidin's interaction with LPS, lipopolysaccharide-binding protein (LBP), and the Toll-like receptor 4 (TLR4) signaling complex.

Main Results:

  • Indolicidin demonstrated good biocompatibility in vitro and in vivo.
  • It significantly improved survival rates and reduced kidney microbial load in murine sepsis models.
  • Indolicidin suppressed M1 macrophage polarization, ROS production, and pro-inflammatory cytokine expression.
  • Transcriptomic data revealed downregulation of inflammation, chemokine signaling, and LPS-response pathways, including key genes like IL-6, CD80, and CD86.
  • Mechanistically, indolicidin bound LPS, interfered with LBP, and reduced CD14 and TLR4/MD2 complex expression, indicating TLR4 pathway modulation.

Conclusions:

  • Indolicidin exhibits dual antimicrobial and immunomodulatory functions beneficial in sepsis.
  • It protects against bacterial and fungal sepsis by reducing microbial burden and suppressing excessive inflammation via TLR4 pathway modulation.
  • Indolicidin represents a potential therapeutic candidate for sepsis treatment.
Keywords:
Candida albicansTLR4 signaling pathwayimmunomodulationindolicidinlipopolysaccharidesepsis

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