Inhibition of soluble epoxide hydrolase attenuates eosinophil recruitment and food allergen-induced gastrointestinal inflammation

Abstract

Prevalence of food allergies in the United States is on the rise. Eosinophils are recruited to the intestinal mucosa in substantial numbers in food allergen-driven gastrointestinal (GI) 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. We investigated the role of sEH in a murine model of food allergy and evaluated the potential therapeutic effect of a highly selective sEH inhibitor (trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]-cyclohexyloxy}-benzoic acid [t-TUCB]). 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. Administration of t-TUCB to SPI-challenged mice inhibited IgE levels and prevented SPI-induced 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. In t-TUCB-treated mice, eosinophilia, mast cell recruitment, and mucus secretion were significantly lower than in untreated mice and SPI-induced loss of junction protein expression was prevented to variable levels. sEH expression in eosinophils was induced by inflammatory mediators TNF-α and eotaxin-1. Treatment of eosinophils with t-TUCB significantly inhibited eosinophil migration, an effect that 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 and GI inflammation including eosinophilia and that inhibition of sEH can attenuate these responses.

Effect Of Dual sEH/COX-2 Inhibition on Allergen-Induced Airway Inflammation

“…VECTASTAIN Elite ABC kit containing biotinylated anti-rabbit IgG (Vector Laboratories, Burlingame, CA), and the Peroxidase AEC (3-amino-9-ethylcarbazole) substrate kit (Vector Laboratories) were used for detection of bound antibodies. Expression of sEH in lungs of OVA-challenged mice (Ge et al, 2016) was detected as described previously (Bastan et al, 2018). In all cases, stained slides were examined using a Nikon Microphot EPI-FL microscope and images were captured with an Olympus DP71 camera.…”

“…Additionally, studies have shown that inhibition of sEH with a selective inhibitor attenuates ovalbumin (OVA)-induced eosinophilia, reduces levels of Th2 cytokines and chemokines, and improves airway resistance and compliance in mice (Yang et al, 2015). Along these lines, our recent studies have shown that expression of sEH is induced by food allergens in the gastrointestinal (GI) tract and that inhibition of sEH attenuates allergen-induced eosinophilia, mast cell recruitment and mucus secretion in the jejunum (Bastan et al, 2018). As such, identification of inhibitors targeting the COX-2 and sEH enzymatic pathways in the context of allergic airway disease is likely to yield valuable information contributing to the development of novel strategies to manage this disease.…”

Carcinogenesis: Failure of resolution of inflammation?

“…Importantly, the sEH eicosanoid pathway has been suggested to be involved in the progression of colorectal cancer, including obesity-associated cancer ( Zhang, Sanidad, & Zhang, 2019 ). Inflammatory mediators, including angiotensin, TNF-α and NF-κB can upregulate sEH expression in immune cells ( Bastan et al, 2018 ). sEH inhibitors (sEHI) downregulate NF-κB and other inflammatory markers leading to decreased pro-inflammatory cytokines and nitric oxide metabolites and upregulates lipoxins to generate resolution ( Schmelzer et al, 2005 ).…”

In vitro and in vivo Metabolism of a Potent Inhibitor of Soluble Epoxide Hydrolase, 1-(1-Propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea

“…Recent studies have yielded a better understanding of the role of sEH in regulating the progression of several diseases in preclinical studies (Luria et al, 2011; Imig, 2012, 2015; Wang et al, 2013, 2018; Ren et al, 2018). The inhibition of sEH demonstrates a promising approach to treat various diseases, including hypertension (Imig et al, 2005; Anandan et al, 2011), inflammation (Davis et al, 2011; Bastan et al, 2018), diabetes (Lorthioir et al, 2012; Hu et al, 2017), neuropathic pain (Hammock et al, 2011; McReynolds et al, 2016; Wagner K. et al, 2017; Wagner K. M. et al, 2017), and central nervous system (CNS) disorders (Simpkins et al, 2009; Ren et al, 2016; Zarriello et al, 2018). Growing evidence suggests that EpFAs reduce endoplasmic reticulum stress as a common underlying mechanism for these therapeutic effects (Yu et al, 2015; Inceoglu et al, 2017).…”