IL-13 induces esophageal remodeling and gene expression by an eosinophil-independent, IL-13R alpha 2-inhibited pathway.
Eosinophilic esophagitis (EE) is an emerging disease associated with both food and respiratory allergy characterized by extensive esophageal tissue remodeling and abnormal esophageal gene expression, including increased IL-13. We investigated the ability of increased airway IL-13 to induce EE-like changes. Mice with pulmonary (but not esophageal) overexpression of IL-13 evidenced esophageal IL-13 accumulation and developed prominent esophageal remodeling with epithelial hyperplasia, angiogenesis, collagen deposition, and increased circumference. IL-13 induced notable changes in esophageal transcripts that overlapped with the human EE esophageal transcriptome. IL-13-induced esophageal eosinophilia was dependent on eotaxin-1 (but not eotaxin-2). However, remodeling occurred independent of eosinophils as demonstrated by eosinophil lineage-deficient, IL-13 transgenic mice. IL-13-induced remodeling was significantly enhanced by IL-13Ralpha2 deletion, indicating an inhibitory effect of IL-13Ralpha2. In the murine system, there was partial overlap between IL-13-induced genes in the lung and esophagus, yet the transcriptomes were divergent at the tissue level. In human esophagus, IL-13 levels correlated with the magnitude of the EE transcriptome. In conclusion, inducible airway expression of IL-13 results in a pattern of esophageal gene expression and extensive tissue remodeling that resembles human EE. Notably, we identified a pathway that induces EE-like changes and is IL-13-driven, eosinophil-independent, and suppressed by IL-13Ralpha2.
Zuo
Li
L
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Fulkerson
Patricia C
PC
Finkelman
Fred D
FD
Mingler
Melissa
M
Fischetti
Christine A
CA
Blanchard
Carine
C
Rothenberg
Marc E
ME
D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004802:Eosinophilia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004941:Esophagitis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D018793:Interleukin-13 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit