The pathogenesis of chronic eosinophilic esophagitis in SHARPIN-deficient mice

Abstract

An increased number of eosinophils in the esophagus is common in several esophageal and systemic diseases, and a prominent feature of eosinophilic esophagitis. Mouse models can provide insight into the mechanisms of eosinophil infiltration and their pathogenic role. SHARPIN-deficient cpdm mice develop a chronic proliferative dermatitis and an esophagitis characterized by epithelial hyperplasia and the accumulation of eosinophils in the serosa, submucosa, lamina propria and epithelium of the esophagus. We conducted a detailed investigation of the pathogenesis of the esophagitis by light microscopy, immunohistochemistry, and gene expression as the mice aged from 4 to 10 weeks. The thickness of the esophageal epithelium and the number of eosinophils in the esophagus both increased with age. There were scattered apoptotic epithelial cells in mice at 6 – 10 weeks of age that reacted with antibodies to activated caspase 3 and caspase 9. The expression of CCL11 (eotaxin-1), IL4, IL13 and TSLP was increased in cpdm mice compared with wild type (WT) mice, and there was no changein the expression of CCL24 (eotaxin-2), IL5 and IL33. The expression of chitinase-like 3 and 4 (YM1 and YM2) proteins, markers of type 2 inflammation, was greatly increased in cpdm mice, and this was replicated in vitro by incubation of WT esophagus in the presence of IL4 and IL13. Immunohistochemistry showed that these proteins were localized in esophageal epithelial cells. The severity of the esophagitis was not affected by crossing SHARPIN-deficient mice with lymphocyte-deficient Rag1 null mice indicating that the inflammation is independent of B and T lymphocytes.

Keratinocyte-specific deletion of SHARPIN induces atopic dermatitis-like inflammation in mice

“…The cornified layer of the epithelium was thickened and there was accumulation of eosinophils in the subepithelial propria mucosae and the basal layer of the epithelium. Changes were similar to those described in Sharpin cpdm/cpdm mice [57].…”

“…Mild hyperplasia and a few apoptotic epithelial cells were observed on the epithelium of the oral cavity. These changes resemble those found in the spontaneous mutant mice [57].…”

The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues

“…Inflammatory infiltrates are also present in the joints, liver, and lung ( Zhang et al, 2009 ) of these mice. Additionally, these mice develop eosinophilic esophagitis ( Chien et al, 2015 ) and have hypoplastic lymphoid tissues ( HogenEsch et al, 1999 ). While systemic immune infiltrates are partially dependent on lymphocytes, dermatitis in these mice is lymphocyte independent, indicating that this is an auto-inflammatory rather than autoimmune process ( Potter et al, 2014 ).…”

Signals from the various immune cells in promoting food allergy-induced eosinophilic esophagitis like disease

“…The monocyte-derived DCs that aggregate in the esophagus have some macrophage features, such as Fc receptors CD64 and FcεRI receptors. They additionally express chitinase-like protein Ym1 which subsequently mediated macrophage activation [7980]. Their primary role is effector T-cell recruitment through chemokine production and promoting chronic esophageal inflammation [80].…”