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Intestinal epithelial specific AhR deficient mice exhibit increased severity of experimentally induced chronic colitis

芳香烃受体 炎症性肠病 结肠炎 炎症 溃疡性结肠炎 医学 免疫系统 免疫学 渗透(HVAC) 内科学 生物 转录因子 疾病 生物化学 基因 物理 热力学
作者
Aisha Qazi,Anoop Kumar,Anchal Sharma,Nathan Calzadilla,Christopher R. Weber,Kai Mongan,Seema Saksena,Pradeep K. Dudeja,Waddah A. Alrefai,Ravinder K. Gill
出处
期刊:The FASEB Journal [Wiley]
卷期号:36 (S1)
标识
DOI:10.1096/fasebj.2022.36.s1.r6171
摘要

Inflammatory Bowel Diseases (IBD), including Crohn's Disease (CD) and ulcerative colitis (UC), are associated with chronic inflammation of the gastrointestinal tract. While it is a multifactorial disease, recently the aryl hydrocarbon receptor (AhR) has been identified as a susceptibility gene for IBD. AhR is a ubiquitously expressed transcription factor and its activation results in xenobiotic detoxification by CYP1A1 and CYP1B1, as well as induction of anti-inflammatory pathways such as IL-10 and IL-22. In the gut, AhR is vital in maintaining immune cell populations, proliferation, and motility. Previous studies utilizing constitutive knock out of AhR in IECs showed exacerbated inflammation in acute DSS model. How intestinal epithelial cell (IEC) AhR deficiency impacts chronic colitis resembling human IBD is not yet known. Here, we investigated the effect of removing of IEC AhR in an inducible manner utilizing DSS induced chronic colitis (resembling Th1/Th17 and Th2 infiltration as seen in CD patients) and elucidated underlying mechanisms.AhRfl/fl x Villin-CreERT mice received intraperitoneal injections of Tamoxifen (AhRΔIECKO ) to induce knockout or the vehicle (WT) for 5 days. The mice were given water or 1.0% DSS for 5 weeks, alternating weekly with water. Distal colon tissue samples were taken for myeloperoxidase (MPO) assay, immunostaining, and histology to assess severity of inflammation. Additionally, distal colon mucosa samples were collected for mRNA and protein expression. Serum was used to assess levels of LPS through ELISA.AhRΔIECKO mice given DSS had increased severity of colitis as evidenced by i) a significant decrease in the colon length when compared to the WT given DSS; ii) an increase in mRNA expression of pro-inflammatory cytokines, IFN- γ and IL-1□; iii) an increase in MPO activity in the distal colon; iv) a significant increase in the spleen to body weight ratio; and v) a significant increase in histological scores. Interestingly, DSS treatment caused an increase in lipopolysaccharide (LPS) in the serum that was significantly higher in AhRΔIECKO as compared to WT indicative of increased paracellular permeability. There were no significant differences observed in the protein expression of Occludin, Claudin-2, and ZO-1 between AhRΔIECKO and WT DSS groups, however AhR KO mice given DSS had significantly increased phosphorylated ERK1/2 (pERK normalized to total ERK) levels which may contribute to the increased permeability and severity of inflammation.Deletion of AhR from intestinal epithelial cells increases severity of chronic colitis associated with increased permeability possibly through ERK1/2 dependent mechanisms.

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