Adipose-derived stem cell exosomes loaded with icariin attenuated M1 polarization of macrophages via inhibiting the TLR4/Myd88/NF-κB signaling pathway

Int Immunopharmacol. 2024 Aug 20:137:112448. doi: 10.1016/j.intimp.2024.112448. Epub 2024 Jun 12.

Abstract

Abnormal macrophage polarization is one of the common pathological bases of various inflammatory diseases. The current research focus involves targeting macrophages to remodel their phenotype as a treatment approach for inflammatory diseases. Notably, exosomes can be delivered to specific types of cells or tissues or inflammatory area to realize targeted drug delivery. Although icariin (ICA) exhibits regulatory potential in macrophage polarization, the practical application of ICA is impeded by its water insolubility, poor permeability, and low bioavailability. Exploiting the inherent advantages of exosomes as natural drug carriers, we introduce a novel drug delivery system-adipose-derived stem cells-exosomes (ADSCs-EXO)-ICA. High-performance liquid chromatography analysis confirmed a loading rate of 92.7 ± 0.01 % for ADSCs-EXO-ICA, indicating the successful incorporation of ICA. As demonstrated by cell counting kit-8 assays, ADSCs-EXO exerted a significantly higher promotion effect on macrophage proliferation. The subsequent experimental results revealed the superior anti-inflammatory effect of ADSCs-EXO-ICA compared to individual treatments with EXO or ICA in the lipopolysaccharide + interferon-gamma-induced M1 inflammation model. Additionally, results from enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, and western blot analyses revealed that ADSCs-EXO-ICA effectively inhibited macrophage polarization toward the M1-type and concurrently promoted polarization toward the M2-type. The underlying mechanism involved the modulation of macrophage polarization through inhibition of the Toll-like receptor 4/myeloid differentiation factor 88/nuclear transcription factor-kappa B signaling pathway, thereby mitigating inflammation. These findings underscore the potential therapeutic value of ADSCs-EXO-ICA as a novel intervention for inflammatory diseases.

Keywords: Anti-inflammatory; Exosomes; Human adipose-derived stem cells; Icariin; Macrophage polarization.

MeSH terms

  • Adipose Tissue / cytology
  • Adipose Tissue / metabolism
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Exosomes* / metabolism
  • Flavonoids* / pharmacology
  • Inflammation
  • Lipopolysaccharides
  • Macrophages* / drug effects
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Differentiation Factor 88* / metabolism
  • NF-kappa B* / metabolism
  • RAW 264.7 Cells
  • Signal Transduction* / drug effects
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Toll-Like Receptor 4* / metabolism

Substances

  • icariin
  • Flavonoids
  • Toll-Like Receptor 4
  • NF-kappa B
  • Myeloid Differentiation Factor 88
  • Anti-Inflammatory Agents
  • Tlr4 protein, mouse
  • Myd88 protein, mouse
  • Lipopolysaccharides