Sotetsuflavone ameliorates Crohn's disease-like colitis by inhibiting M1 macrophage-induced intestinal barrier damage via JNK and MAPK signalling

  • Eur J Pharmacol. 2023 Feb 5:940:175464. doi: 10.1016/j.ejphar.2022.175464.
Sitang Ge  1 ,  Yating Yang  2 ,  Lugen Zuo  2 ,  Xue Song  3 ,  Hexin Wen  4 ,  Zhijun Geng  5 ,  Yifan He  2 ,  Zilong Xu  2 ,  Huatao Wu  2 ,  Mengdi Shen  2 ,  Yuanyuan Ge  6 ,  Xuejun Sun  7
Affiliations
  • 1. Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China; Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China.
  • 2. Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China; Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical College, Bengbu, China.
  • 3. Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical College, Bengbu, China; Department of Central Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, China.
  • 4. Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China.
  • 5. Department of Central Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, China.
  • 6. Department of Colorectal Surgery, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
  • 7. Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China. Electronic address: [email protected].
PMID: 36566007 DOI: 10.1016/j.ejphar.2022.175464
Abstract

Objectives: Intestinal inflammation and intestinal barrier dysfunction are two important pathological changes in Crohn's disease (CD). Sotetsuflavone (SF) is a natural monomeric herbal compound with anti-inflammatory and cytoprotective effects that is mostly nontoxic. The effect of SF on CD-like spontaneous colitis was investigated in this study.

Methods: IL-10-/- mice were used as a CD model and were administered different doses of SF. Lipopolysaccharide (LPS) plus IFN-γ-induced macrophages (RAW264.7) and a coculture system (RAW264.7 and organoids) were used in vitro. The protective effects of SF against CD-like colitis and macrophage differentiation and the mechanisms were evaluated.

Results: SF treatment markedly improved spontaneous colitis in the CD model, as shown by the following evidence: reductions in the DAI, macroscopic scores (3.63 ± 1.30), colonic tissue inflammatory scores (2 ± 0.76) and proinflammatory factor levels and the attenuation of colon shortening (8 ± 0.93 cm) and weight loss (1.75 ± 1.83 g). Decreased intestinal permeability and intestinal Bacterial translocation rates provided evidence of the protective effect of SF on intestinal barrier function. We also found that SF suppressed M1 macrophage-induced inflammatory responses. In the coculture system of mouse colonic organoids and RAW264.7 cells, SF significantly ameliorated M1 macrophage-induced intestinal epithelial damage. In addition, SF inhibited JNK and MAPK (p38) signalling in both IL-10-/- mice and LPS plus IFN-γ-induced macrophages (RAW264.7).

Conclusions: The protective effects of SF against CD-like colitis may be achieved partially by inhibiting M1 macrophage-induced intestinal barrier damage via JNK and p38 signalling. SF may have therapeutic potential for treating CD, especially considering its safety.

Keywords
Crohn's disease; Intestinal barrier function; MAPK; Macrophages; Sotetsuflavone.
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