Abstract
ABSTRACTThe intestinal epithelium is continuously exposed to deleterious environmental factors that might cause aberrant immune responses leading to inflammatory disorders. However, what environmental factors might contribute to disease are poorly understood. Here, to overcome the lack of in vivo models suitable for screening of environmental factors, we used zebrafish reporters of intestinal inflammation. Using zebrafish, we interrogated the immunomodulatory effects of polyfluoroalkyl substances, which have been positively associated with ulcerative colitis incidence. Exposure to perfluorooctanesulfonic acid (PFOS) during 2,4,6-trinitro-benzene sulfonic acid (TNBS)-induced inflammation enhanced the expression of proinflammatory cytokines as well as neutrophil recruitment to the intestine of zebrafish larvae, which was validated in the TNBS-induced colitis mouse model. Moreover, PFOS exposure in mice undergoing colitis resulted in neutrophil-dependent increased intestinal permeability and enhanced PFOS translocation into the circulation. This was associated with a neutrophil-dependent expansion of systemic CD4+ T cells. Thus, our results indicate that PFOS worsens inflammation-induced intestinal damage with disruption of T-cell homeostasis beyond the gut and provides a novel in vivo toolbox to screen for pollutants affecting intestinal homeostasis.
Highlights
Inflammatory bowel diseases (IBDs), encompassing Crohn’s disease and ulcerative colitis, are multifactorial diseases characterized by chronic inflammation of the gastrointestinal tract
We took advantage of the TgBAC(cldn15la:GFP) (Alvers et al, 2014) crossed to the Tg(lysC:DsRed2) (Hall et al, 2007) to generate a double reporter zebrafish line that enables the visualization of neutrophil recruitment to the intestine, which is considered a hallmark of intestinal inflammation
Because we showed that neutrophil numbers were increased in the intestine of perfluorooctanesulfonic acid (PFOS)-exposed mice during intestinal inflammation, we asked whether neutrophil depletion might restore the systemic CD4+ T-cell levels in these mice
Summary
Inflammatory bowel diseases (IBDs), encompassing Crohn’s disease and ulcerative colitis, are multifactorial diseases characterized by chronic inflammation of the gastrointestinal tract. The etiology of IBD has not been fully elucidated, but it is believed to develop as an active and continuing inflammatory response triggered by environmental factors in genetically susceptible hosts. The prevalence of IBD has historically been higher in Western countries, it is a global disease, with the highest increase in incidence in newly developing countries (Kaplan and Ng, 2017). This shift in IBD epidemiology reinforces the notion that environmental factors play an important role in disease pathogenesis (Ananthakrishnan et al, 2018). A major challenge in the field of mucosal immunology is the identification of environmental factors that might disrupt intestinal homeostasis and lead to intestinal inflammation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
