Inhibition of Soluble Epoxide Hydrolase Attenuates Food Allergen‐induced Eosinophil Recruitment and Gastrointestinal Inflammation

Abstract

The prevalence of food allergies is on the rise, affecting nearly 4–6% of the population in the US and impacting their daily life in various ways. Although present in the normal gastrointestinal (GI) mucosa under homeostatic conditions, eosinophils are recruited to the intestinal mucosa in increased numbers in food allergy and contribute to inflammation. Soluble epoxide hydrolase (sEH) is known to play a pro‐inflammatory role during inflammation by metabolizing anti‐inflammatory epoxyeicosatrienoic acids (EETs) to pro‐inflammatory diols. In the current study, the role of sEH in a murine model of food allergy was investigated and the potential therapeutic effect of a highly selective sEH inhibitor (t‐TUCB) was evaluated. Oral exposure of mice on a soy‐free diet to soy protein isolate (SPI) induced expression of intestinal sEH, increased circulating total and antigen‐specific IgE levels and caused significant weight loss. Additionally, SPI induced GI inflammation characterized by increased recruitment of eosinophils and mast cells, elevated eotaxin‐1 levels, mucus hypersecretion and decreased epithelial junction protein expression. Administration of t‐TUCB to SPI‐challenged mice not only inhibited IgE levels and prevented SPI‐induced weight loss but also significantly decreased eosinophilia, mast cell recruitment and mucus secretion relative to untreated mice while SPI‐induced loss of junction protein expression was prevented to variable levels. Inflammatory mediators such as TNF‐α and eotaxin‐1 were found to induce sEH expression in eosinophils. Treatment of eosinophils with t‐TUCB significantly inhibited eosinophil migration, an effect which was mirrored by treatment with 11,12‐EET, by inhibiting intracellular signaling events such as ERK (1/2) activation and eotaxin‐1‐induced calcium flux. These studies suggest that sEH induced by soy proteins promotes allergic responses including eosinophilic GI inflammation and that inhibition of sEH can attenuate these allergen‐induced responses.Support or Funding InformationSupport was provided in part by National Institute of Environmental Health Sciences and National Institute of Diabetes and Digestive and Kidney Diseases to B.D.H. and by the University of Minnesota College of Veterinary Medicine Research Office, Minnesota Agricultural Experiment Station, and General Ag Research Funds to R.J.W.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.