S100A8/A9 (Calprotectin) alarmin is indispensable for the development of eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a rare, but emerging, allergic disease, characterized by a type 2 immune response and fibrosis that can develop into esophageal dysfunction. Calprotectin has been implicated in various allergic diseases. It functions as an alarmin or danger associated molecular pattern, thereby triggering an immune cascade, and also exerts microbiome-modulating effects. Here, we investigated the role of calprotectin in the development and propagation of oxazolone-induced murine EoE, which well mimics the hallmarks of human disease. A prominent increase in esophageal expression of S100A8/A9 was noted in several models of EoE, in both differentiated epithelial cells and infiltrating lamina propria immune cells, such as monocytes, neutrophils and eosinophils. S100a9-/- mice were protected from oxazolone-induced EoE, as manifested by the significant reduction in thickening of esophageal epithelia and lamina propria, epithelial hyperplasia, fibrosis and accumulation of cytokeratin 14 (CK14)+ non-differentiated epithelial cells. Notably, type 2 immune response in S100a9-/- mice was diminished, as marked by the reduction in eosinophil accumulation, a hallmark of EoE disease, and esophageal expression of key immune mediators such as TSLP, IL-33, IL-13 and IL-5. Additionally, mining from single-cell RNA seq data on human esophageal biopsies suggested the local release of calprotectin by dying S100A8/A9+ differentiated epithelial cells in patients with active disease. Collectively, these results outline a deleterious role for calprotectin in EoE development and propagation.