Toll-like receptor 4 regulates intestinal fibrosis via cytokine expression and epithelial-mesenchymal transition

• Published in: Scientific reports Vol. 10; no. 1; p. 19867
• Main Authors: Jun, Yu Kyung, Kwon, So Hyun, Yoon, Hee Tae, Park, Hyunsun, Soh, Hosim, Lee, Hyun Jung, Im, Jong Pil, Kim, Joo Sung, Kim, Ji Won, Koh, Seong-Joon
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-11-2020; Nature Publishing Group
• Subjects: 631/250; 692/4020; Animals; Cell Line; Colitis; Collagen; Colon; Colonic Diseases - chemically induced; Colonic Diseases - genetics; Colonic Diseases - immunology; Colonic Diseases - pathology; Cytokines - metabolism; Dextran; Dextran sulfate; Dextran Sulfate - adverse effects; Disease Models, Animal; Epithelial cells; Epithelial-Mesenchymal Transition; Fibrosis; Gene Expression Regulation - drug effects; HCT116 Cells; Humanities and Social Sciences; Humans; Interleukin-12 Subunit p40 - metabolism; Intestine; Macrophages; Macrophages, Peritoneal - metabolism; Matrix metalloproteinase; Mesenchyme; Metalloproteinase; Metastases; Mice; multidisciplinary; Peritoneum; Science; Science (multidisciplinary); Signal Transduction; siRNA; Stenosis; TLR4 protein; Toll-Like Receptor 4 - genetics; Toll-like receptors; Transcription; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-76880-y

Intestinal fibrosis induced by chronic and recurrent colitis, which is exacerbated by bowel stenosis, stricture, and obstruction, is challenging to treat. Toll-like receptor 4 (TLR4) stimulates innate and acquired immunity in response to specific microbial components, but the role of TLR4 in intestinal fibrosis is largely unknown. We investigated its role in intestinal fibrosis using not only a murine fibrosis model but also human myofibroblasts and intestinal epithelial cells. Colon fibrosis was induced in TLR4-deficient (TLR4
−/−
) mice and its wild-type counterparts with 3% dextran sulfate sodium. Absence of TLR4 gene attenuated chronic inflammation and colonic macrophages infiltration; intestinal fibrosis and collagen deposition were suppressed. Also, the production of tumor necrosis factor-α, interleukin-12p40, and transforming growth factor-β was reduced in TLR4-deficient peritoneal macrophages. TLR4 was silenced in CCD-18Co cells by small interfering RNA (siRNA), and matrix metalloproteinase-1, tissue inhibitor of metalloproteinase, and collagen α1 expression was evaluated. Role of TLR4 in epithelial-mesenchymal transition (EMT) was evaluated in HCT116 cells. Suppression of TLR4 transcription by siRNAs affected myofibroblasts activity, collagen synthesis, and EMT in the human cancer cell line. Thus, we suggest that TLR4 can be an essential mediator in intestinal chronic inflammation and fibrosis, indicating that TLR4 signaling is a potential therapeutic target for intestinal fibrosis.