Fenretinide regulates macrophage polarization to protect against experimental colitis induced by dextran sulfate sodium

Bioengineered. 2021 Dec;12(1):151-161. doi: 10.1080/21655979.2020.1859259.

Abstract

Fenretinide (4-HPR), a synthetic retinoid, has attracted attention for its anti-inflammation activity. However, few studies have evaluated the effects of 4-HPR on ulcerative colitis (UC). The present study was performed to investigate the therapeutic effects of 4-HPR on UC, and to explore the mechanisms mainly focused on macrophage polarization involved in this progress. Intraperitoneally administered 4-HPR particularly at dose of 100 mg/kg obviously alleviated UC symptoms and restrained the mRNA expression of colonic IL-1β, IL-6, and TNF-α in dextran sulfate sodium (DSS)-induced mice. Further analysis showed that 4-HPR decreased the mRNA expression of M1 macrophage markers IL-12 and iNOS, while increased M2 macrophage markers Ym1, Arg1 and MRC1 in colonic tissue of mice received DSS. Consistently, an in vitro study revealed that 4-HPR decreased inflammatory response and M1 polarization, while enhanced M2 polarization in LPS-induced RAW264.7 cells. Interestingly, 4-HPR remarkably activated PPAR-γ which was an important regulator of macrophage polarization both in colonic tissue of UC mice and in LPS-induced RAW264.7 cells. Furthermore, these effects of 4-HPR in vivo and in vitro including anti-inflammation and modulation of macrophage polarization were partially abolished by treatment with PPAR-γ antagonist GW9662, indicating that 4-HPR activated PPAR-γ to exert its activities. Taken together, this study demonstrated that 4-HPR might be a potent anti-UC agent that works by regulating macrophage polarization via PPARγ.

Keywords: Fenretinide; PPAR-γ; RAW264.7 cells; macrophage polarization; ulcerative colitis.

MeSH terms

  • Animals
  • Cell Polarity / drug effects*
  • Colitis, Ulcerative / chemically induced
  • Colitis, Ulcerative / metabolism
  • Colitis, Ulcerative / pathology*
  • Colon / drug effects
  • Colon / pathology
  • Dextran Sulfate / adverse effects
  • Disease Models, Animal
  • Fenretinide / pharmacology*
  • Macrophages / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protective Agents / pharmacology*
  • RAW 264.7 Cells

Substances

  • Protective Agents
  • Fenretinide
  • Dextran Sulfate

Grants and funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.