{"doi":"10.1111/all.16592","title":"Involvement of <scp>IL</scp>‐13‐Induced Dysregulation of <scp>BDNF</scp>‐<scp>NTRK2</scp> Pathway in Symptoms of Eosinophilic Esophagitis","abstract":"Eosinophilic esophagitis (EoE) is a chronic, type 2 immune-mediated inflammatory disease of the esophagus characterized by symptoms (e.g., dysphagia, heartburn, and chest pain) and esophageal eosinophilia (≥ 15 eosinophils per high-power field) [1]. A recent benralizumab clinical trial revealed a discordance between eosinophil counts and symptom severity, as reducing eosinophils did not improve symptoms [2]. EoE symptoms significantly impair quality of life, yet their underlying mechanisms remain unclear. Recent studies indicate that gene expression changes in both epithelial and non-epithelial cells correlate with symptom severity, whereas transient receptor potential vanilloid 1 (TRPV1, pain-associated gene) and mast cell interactions contribute to pain, highlighting the need for further research [3, 4]. Increased awareness of EoE has led to more esophageal biopsies during endoscopy for indications beyond esophageal dysfunction. This often uncovers incidental histologic eosinophilia in asymptomatic subjects (i.e., asymptomatic esophageal eosinophilia, aEE) sharing similar endoscopic and histologic features with EoE [5]. Therefore, we hypothesized that EoE and aEE would have distinct esophageal gene expression changes linked to EoE symptoms. We aimed to determine the molecular profiles of EoE and aEE, elucidate symptom-associated gene expression changes, and investigate the role of IL-13 in neuronal excitability using in vitro assays with human induced pluripotent stem cell–derived sensory neurons (iPSC-SN). We enrolled EoE and aEE (n = 20, each; informed consent was obtained from all participants) who were diagnosed during a medical health check-up at Osaka Metropolitan University Hospital. Despite their symptomatic divergence, EoE and aEE had no significant clinical differences (Table S1). First, we evaluated the molecular profiles using the EoE Diagnostic Panel (EDP) and compared them to those of a historical cohort [6]. Using an EDP score reflecting EoE activity, we found similar scores between EoE and aEE, consistent with peak eosinophil counts, though both differed significantly from normal controls (Figure 1A). Heatmaps revealed the EoE hallmark gene signature in aEE (Figure 1B). The EoE esophageal transcriptome was remarkably conserved in aEE, and no differences were found between the two groups, indicating that, aside from symptomatology, EoE and aEE share basic characteristics and molecular profiles among subjects. Next, we focused on the neuropathic genes (Table S2) outside of the EoE transcriptome. Of 94 genes, we identified 11 differentially expressed genes (DEGs) in EoE versus aEE (≥ 2-fold change, FDR p < 0.05) (Figure 1C). Given their correlation with the EoE transcriptome and functional pathway (Figure 1D,E), we focused on brain-derived neurotrophic factor (BDNF) and neurotrophic receptor tyrosine kinase 2 (NTRK2). Both genes, key to neuropathic pathways, were upregulated in EoE compared to aEE and correlated with each other (Figure 1F,G). Immunofluorescence of symptomatic EoE tissue shows that BDNF and NTRK2 co-localize in the lamina propria, with tubulin beta-3 staining confirming their proximity to peripheral nerve fibers (Figure 1H,I), suggesting that the BDNF–NTRK2 pathway may contribute to EoE symptoms. Finally, we tested whether IL-13 regulates neuronal excitability and transcriptional changes of BDNF and NTRK2 using human iPSC-SN (Figure 2A). Notably, IL-13, central to EoE pathogenesis, increased neuronal firing in a dose-dependent manner compared to that of vehicle-treated cells as measured by the microelectrode array (Figure 2B,C). Pretreatment with dupilumab (a monoclonal antibody targeting IL-4Rα to block IL-4 and IL-13 signaling) significantly reduced excitability (Figure 2D). We also observed IL-13–induced upregulation of BDNF (p < 0.0001) and NTRK2 (p = 0.0016) in iPSC-SNs, which was effectively suppressed by pretreatment with dupilumab (Figure 2E). Collectively, these findings suggest that IL-","journal":"Allergy","year":2025,"id":533697,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1415889,"name":"Akinari Sawada","orcid":"0000-0002-0590-3693","position":1,"is_corresponding":false},{"id":1416332,"name":"Yuki Maekawa","orcid":null,"position":2,"is_corresponding":false},{"id":1416333,"name":"Mari Yamaguchi","orcid":null,"position":3,"is_corresponding":false},{"id":1415890,"name":"Shingo Yamada","orcid":"0000-0001-9250-6241","position":4,"is_corresponding":false},{"id":1243893,"name":"Kazuhiro Matsuyama","orcid":null,"position":5,"is_corresponding":false},{"id":349883,"name":"Mark Rochman","orcid":"0000-0002-0818-927X","position":6,"is_corresponding":false},{"id":237537,"name":"Marc E. Rothenberg","orcid":"0000-0001-9790-6332","position":7,"is_corresponding":false},{"id":191146,"name":"Xiaobo Han","orcid":null,"position":8,"is_corresponding":false},{"id":1415891,"name":"Naoki Matsuda","orcid":"0000-0002-6567-0721","position":9,"is_corresponding":false},{"id":492466,"name":"Ikuro Suzuki","orcid":"0000-0002-1653-1450","position":10,"is_corresponding":false},{"id":1415892,"name":"Fumio Tanaka","orcid":"0000-0002-9186-1249","position":11,"is_corresponding":false},{"id":796349,"name":"Yasuhiro Fujiwara","orcid":"0000-0002-1229-5446","position":12,"is_corresponding":false},{"id":445119,"name":"Tetsuo Shoda","orcid":"0000-0001-8337-5438","position":13,"is_corresponding":false},{"id":1086320,"name":"Kasumi Osonoi","orcid":null,"position":0,"is_corresponding":true}],"reference_count":6,"raw_metadata":null,"created_at":"2026-07-19T02:51:43.451278Z","pmid":"40358555","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}