Abstract
Inflammatory bowel disease (IBD) is a refractory chronic inflammatory illness of the gastrointestinal (GI) tract. Macrophage exerts an important role in IBD development. QKI, as an RNA binding protein, was related with inflammatory responses in bacterial infections by regulating the polarization of macrophages. Therefore, we suspected that QKI-regulated macrophages have the potential to play a certain role in IBD and the underlying mechanism. Our results demonstrated that the mice with macrophage-specific deletion of QKI induced with dextran sodium sulfate (DSS) are more susceptible to IBD development, exhibited a severe leaky gut barrier phenotype and higher intense oxidative stress, which are rescued by treating with butylated hydroxyanisole (BHA), an agonist of NRF2. Mechanically, we observed that Keap1 mRNA in the nucleus was exported to the cytoplasm after LPS stimuli in parallel with QKI reductions, and the removal of QKI by shRNA facilitated Keap1 mRNA nuclear exporting and expression in cytoplasm, consequently NRF2 activation in nucleus was weakened, and led to the impaired antioxidant abilities. In addition, mice models of fecal microbiota transplant (FMT) and the co-culturing of mice epithelia cells with feces derived from the DSS-treated QKI-deficit mice revealed consistently aggravated colitis along with a severe oxidative stress; 16S sequencing analysis substantiated the altered compositions of commensal bacteria too. Overall, the current study represents the first effort to explore the anti-oxidant role of QKI in the intestinal macrophage via post-transcriptional regulation of Keap1 mRNA localization and the relevant NRF2 antioxidant signaling, and the disproportional changes in the microbiota were attributable to the mediation of pathogenic damage in the IBD development of QKI-deficit mice.
Highlights
Inflammatory bowel disease (IBD) is a refractory chronic nonspecific inflammation disease of the colon and small intestine, including ulcerative colitis (UC) andCrohn’s disease (CD)[1]
In order to explore the potential role of QKI in the pathogenesis of IBD, we studied the QKI expression in the intestinal macrophages of active lesions and uninflamed mucosa from patients with UC and colitis (UC) andCrohn’s disease (CD)
The expression of QKI in CD11b+F4/80+ monocytes was significantly increased in the dextran sodium sulfate (DSS)-induced colitis mouse models, which was detected by flow cytometry (Supplementary Fig. 1C)
Summary
Inflammatory bowel disease (IBD) is a refractory chronic nonspecific inflammation disease of the colon and small intestine, including ulcerative colitis (UC) and. Accumulating evidence supports that epithelial defects with the mucus layer destruction, disturbance of commensal or pathogenic bacteria, as well as immune imbalance together contribute to the development of IBD2–5. Conventional treatments including anti-inflammatory and immunosuppressive therapies fail to prevent the deterioration of IBD6. Better understanding the pathology and therapeutic scheme of IBD is urgently required. In the gastrointestinal (GI) hollow organ, the intestinal epithelia act as a physical barrier that separates the intestinal microbiota from the underlying tissues to prevent bacterial infiltration and subsequent inflammation[7,8]. Official journal of the Cell Death Differentiation Association
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