Tanshinone I limits inflammasome activation of macrophage via docking into Syk to alleviate DSS-induced colitis in mice

Mol Immunol. 2024 Sep:173:88-98. doi: 10.1016/j.molimm.2024.07.007. Epub 2024 Jul 31.

Abstract

Tanshinone I (Tan I) has been proven to exert an anti-inflammatory effect, but the complete mechanism remains unclear. In this study, Tan I was described to have no effect on Syk expression in resting or LPS-stimulated macrophages ex vivo, but dramatically suppressed Syk phosphorylation and CD80, CD86, and IL-1β expression of macrophages. The inflammatory activity of macrophages in ApoC3-transgenic (ApoC3TG) mice is upregulated by Syk activation. Tan I was determined to downregulate Syk phosphorylation and inflammatory activity of macrophages in ApoC3TG mice, both ex vivo and in vivo. Intraperitoneal injection of Tan I (4 mg/kg) effectively alleviated DSS-induced colitis in mice, accompanying with suppressing the activation of intestinal macrophages. Mechanistically, Tan I-treated macrophages exhibited a decrease in cytoplasmic ROS, NLRP3, GSDMD, and IL-1β, which suggested that the alternative pathway of inflammasome activation in macrophages was suppressed. The SPR assay demonstrated that Tan I bound to Syk protein with a dissociation constant (KD) of 2.473 × 10-6 M. When Syk expression was knocked down by its shRNA, the inhibitory effects of Tan I on macrophages were blocked. Collectively, Tanshinone I effectively alleviated DSS-induced colitis in mice by inhibiting Syk-stimulated inflammasome activation, hence suppressing the inflammatory activity of macrophages.

Keywords: Colitis; Inflammasome; Macrophage; Syk; Tanshinone I.

MeSH terms

  • Abietanes* / pharmacology
  • Animals
  • Colitis* / chemically induced
  • Colitis* / drug therapy
  • Colitis* / immunology
  • Colitis* / metabolism
  • Dextran Sulfate*
  • Inflammasomes* / drug effects
  • Inflammasomes* / metabolism
  • Macrophages* / drug effects
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Syk Kinase* / metabolism

Substances

  • Syk Kinase
  • Abietanes
  • tanshinone
  • Inflammasomes
  • Dextran Sulfate
  • Syk protein, mouse