Siglec‐F Inhibition Reduces Esophageal Eosinophilia and Angiogenesis in a Mouse Model of Eosinophilic Esophagitis

Abstract

Objectives Eosinophilic esophagitis (EoE) is a disorder characterized histologically by tissue eosinophilia. Sialic acid–binding immunoglobulin-like lectin (Siglec-F) is a receptor highly expressed on mouse eosinophils and mediates eosinophilic apoptosis. We investigated whether administration of an anti-Siglec-F Ab would reduce esophageal eosinophilic inflammation and remodeling in a mouse model of egg ovalbumin (OVA)–induced EoE. Subjects and Methods Three groups of mice were studied (no OVA, OVA + anti-Siglec-F Ab, and OVA + isotype control Ab). Mice were sensitized intraperitoneally and then challenged chronically with intraesophageal OVA. Levels of esophageal eosinophils and features of remodeling (angiogenesis, vascular endothelial growth factor expression, deposition of fibronectin, basal zone hyperplasia, and fibrosis) were quantitated by immunohistochemistry and image analysis. Results Administration of an anti-Siglec-F Ab to OVA-challenged mice significantly reduced levels of esophageal eosinophils, down to levels noted in non-OVA-challenged mice. The anti-Siglec-F Ab also reduced features of OVA-induced remodeling, including angiogenesis, basal zone hyperplasia, and fibronectin deposition. The reduced angiogenesis in anti-Siglec-F Ab-treated mice was associated with reduced numbers of vascular endothelial growth factor–positive cells in the esophagus. The anti-Siglec-F antibody did not significantly reduce esophageal fibrosis as assessed by trichrome staining. Conclusions Administration of an anti-Siglec-F antibody significantly decreased the number of eosinophils in the esophagus in a mouse model of OVA-induced EoE. The reduction in eosinophilic inflammation was associated with a significant decrease in levels of angiogenesis, deposition of fibronectin, and basal zone hyperplasia. Studies in this pre-clinical model of EoE suggest that Siglec-F (and its human paralog Siglec-8) may be novel therapeutic targets to reduce eosinophilic inflammation in EoE.

Tissue remodeling in eosinophilic esophagitis

“…Siglecs are expressed by a number of immune cells, including eosinophils, and Siglecs are involved in regulating inflammation. Rubenstein et al (133) demonstrated that anti-Siglec-F antibody decreased eosinophil infiltration, angiogenesis, fibronectin deposition, and basal zone hyperplasia in a mouse model of EoE. These findings suggest that Siglec-8, the human paralog of Siglec-F, might be a therapeutic target for improving tissue remodeling in patients with EoE.…”

“…The ovalbumin-challenged mouse model does not involve genetic manipulations. Rather, BALB/c mice are sensitized to ovalbumin by intraperitoneal administration of the egg allergen, followed by the chronic intraesophageal administration of ovalbumin (133). These animals also develop esophageal eosinophilia and remodeling.…”

Local hypersensitivity reaction in transgenic mice with squamous epithelial IL-5 overexpression provides a novel model of eosinophilic oesophagitis

“…Oesophageal studies in the mouse have bifurcated based on the experimental strategies utilised to generate these models of EoE: (1) Sensitisation/local challenge approaches in which wild-type mice undergo a primary sensitisation event to allergen (and/or a contact irritant) followed by a secondary topical challenge of the oesophagus with the same agent 3 6 7. (2) Transgenic overexpression in mice of candidate inflammatory genes identified from clinical studies of EoE patients 5 37.…”

Siglec-mediated regulation of immune cell function in disease

“…The impact of eosinophil depletion on allergic inflammatory diseases has been explored most directly in mouse models using antibodies to Siglec-F, which effectively deplete eosinophils from blood and tissues 122 . Using this approach, depletion of eosinophils has been documented to significantly reduce pathology in models of allergic rhinitis 123 , esophageal eosinophilia 124 , and allergen induced eosinophil airway remodeling 125 . A similar approach has been used to demonstrate a beneficial effect of eosinophil depletion on allergen induced intestinal inflammation 125 .…”