Loss of QKI in macrophage aggravates inflammatory bowel disease through amplified ROS signaling and microbiota disproportion

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.

The Quaking RNA‐binding proteins as regulators of cell differentiation

“…An important foam cell marker, Scavenger receptor A, was found to be directly targeted and repressed by QKI during monocyte differentiation (Wang et al, 2015). In addition, functions for QKI have also been implicated in mature macrophages (L. W. Wang, Zhai, et al, 2021), re-enforcing the notion that QKI participates in the differentiation and maintenance of macrophage phenotypes.…”

Physiologically Inspired Mucin Coated Escherichia coli Nissle 1917 Enhances Biotherapy by Regulating the Pathological Microenvironment to Improve Intestinal Colonization

“…These physiological factors are responsible for the low survival rate and limited intestinal colonization of probiotics. , More importantly, pathological conditions in IBD can also seriously impede the colonization of probiotics. For example, there is a high concentration of reactive oxygen species (ROS) in the pathological microenvironment. , ROS have a strong oxidation effect on lipids and proteins on the surface of probiotics, which can cause major damage to the cell wall of bacteria and lead to their inactivation. − In addition, bacteria usually colonize in the mucus layer, which is essential for maintaining the intestinal mucosal barrier under physiological conditions. , However, because the mucus layer in the inflammatory site is often exhausted and the intestinal mucosal barrier badly damaged, , oral probiotics may pass through the intestinal barrier into the bloodstream, causing dangerous side effects such as bacterial translocation. , These problems can prevent probiotics from reaching the intestinal tract in a sufficient amount of active form to colonize the intestinal tract and to have good therapeutic effects. As such, the ability to resist the adverse physiological and pathological conditions in the gastrointestinal tract and the ability to adhere to intestinal mucosa are important factors for the colonization of probiotics in the intestine.…”

Manipulating Microbiota in Inflammatory Bowel Disease Treatment: Clinical and Natural Product Interventions Explored

“…Macrophages are a double-edged sword, as their excessive activation can lead to inflammatory activation mediated by microbiota through the secretion of LPS [ 31 ]. Studies have shown that changes in gut microbiota mediated by macrophage dysfunction result in higher susceptibility to IBD [ 32 , 33 ]. The components of the local tissue microenvironment, such as cytokines, microbiota, microbial products, and other immune and stromal cells, more or less determine the macrophage response [ 28 ].…”