Toll-like receptor 4 (TLR4) deficiency aggravates dextran sulfate sodium (DSS)-induced intestinal injury by...

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that causes long-lasting inflammation and ulcers in the human digestive tract. The repair role of TLR4 in the intestinal epithelium is still unknown.

By comparing to wild-type (WT) mice, Toll-like receptor 4 (TLR4)-knockout mice (TLR4-KO) were used as dextran sulfate sodium (DSS)-induced colitis models to explore the role of TLR4 signaling in intestinal injury. High-throughput RNA-Seq, RT-qPCR and ELISA were performed to screen and verify key differences in gut genes between WT and TLR4-KO mice. Functional study of core dysregulated factors was performed in intestinal cell lines.

We found that DSS-induced intestinal injury was aggravated by LPS (TLR4 agonist) and TLR4-KO. When compared to WT mice, IL6, CCL2, CSF3, IL11, Ccnb1, Ccnd1 and TNF-α significantly decreased and Fas and FasL have increased in the gut of TLR4-KO mice. IL6, CCL2, CSF3, Fas and FasL have all increased in CT-26 cells treated with LPS. Combined with the above data and KEGG enrichment, it can be assumed that TLR4-KO might aggravate DSS-induced intestinal damage by attenuating cell cycle, cytokine-cytokine receptor interaction, and Toll-like receptor signaling pathway, and enhancing the apoptosis pathway. In the functional study of core dysregulated factors, it was found that LPS, IL6, IL11, CSF3, CCL2, S100A8, S100A9 and Mmp3 have improved viability of colon cancer cell lines and decreased apoptosis rate of mouse colon cancer cells when these were treated with DSS. However, Jo-2 (Fas agonistic monoclonal antibody) played the opposite role in colon cancer cells treated with DSS.

TLR4 had a repairing effect on DSS-induced intestinal damage and it up-regulate IL6, CCL2 and CSF3. Fas and FasL enhanced DSS-induced colon injury in mice, but might have little to do with TLR4 signaling.