Altered TGFβ signaling in non-hematopoietic cells leads to eosinophilic esophagitis.

Abstract

Abstract Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease characterized by esophageal inflammation and dysfunction. Among the top ten single nucleotide polymorphisms (SNPs) that are associated with EoE susceptibility, approximately one third are in genes that encode proteins involved in transforming growth factor beta (TGFβ) signaling. Patients and mice heterozygous for a mutation in the kinase domain of TGFβR1 (TGFBR1M318R+/−) exhibit cardiovascular, skeletal, pulmonary, and immune manifestations of Loeys-Dietz Syndrome (LDS). Immune manifestations of LDS include elevated serum IgE against food antigens and an increased likelihood of developing EoE that is characterized by esophageal dilation, food impaction, basal cell hyperplasia, and an inflammatory infiltrate composed of eosinophils, mast cells, T cells, type 2 innate lymphoid cells (ILC2), and antigen presenting cells. How altered TGFβ signaling leads to EoE is unknown. We made bone marrow chimeras to determine which cells are responsible for the development of EOE. We found that altered TGFβ signaling in radio-resistant non-hematopoietic cells was both necessary and sufficient to cause EoE. Moreover, the development of EoE was not predicated on altered TGFβ signaling in the hematopoietic effector cells. Using RNASeq and immuno-histochemistry analyses we show that altered TGFβ signaling in esophageal epithelial cells results in the expression of cytokines, chemokines, and adhesion molecules that facilitate the recruitment, activation, and accumulation of eosinophils, mast cells, T cells, and ILC2. Targeting these inflammatory mediators in vivo should have therapeutic potential for patients suffering with EoE.