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Войти в исследования Cellular and molecular gastroenterology and hepatology · 2026
Thymic Stromal Lymphopoietin-Driven B-Cell Hyperactivation Impairs Intestinal Epithelial Homeostasis Predisposing to Enterocolitis in Hirschsprung Disease.
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He Shiwei, Zheng Ziyi, Meng Lingdu, Lin Lin, Wang Zhe, Zhou Jie, Lin Jiaye, Yang Ran, Lin Yang, Huang Yanlei, Huang Zhihong, Huang Yanbing, Chen Yingjian, Li Lizhi, Chen Feng, Dong Rui
Аннотация
BACKGROUND & AIMS: Hirschsprung-associated enterocolitis, a lethal complication of Hirschsprung's disease-a prevalent congenital disorder with high morbidity-has a poorly understood pathogenesis. We investigated how aberrant immune-stromal crosstalk drives mucosal injury in Hirschsprung's disease.
METHODS: Integrated single-cell RNA sequencing, spatial transcriptomics, bulk RNA sequencing, and proteomics were performed using human Hirschsprung's disease tissues. Validation was conducted using murine Hirschsprung-associated enterocolitis (Ednrb-/-) models, flow cytometry, multiplex immunohistochemistry, in vitro B-cell stimulation, epithelial coculture, rescue experiments with the thymic stromal lymphopoietin inhibitor baicalein, and ex vivo intestinal organoid assays.
RESULTS: We identified significant expansion and hyperactivation of B cells that colocalized with epithelial barrier defects in Hirschsprung's disease segments. Multiomics analysis revealed an activated phenotype in these naive and memory B cells, characterized by the upregulation of B lymphocyte kinase, B cell linker, and proliferating cell nuclear antigen, which may contribute to impaired epithelial homeostasis. Crucially, we identified profibrotic thymic stromal lymphopoietin+ fibroblasts enriched in Hirschsprung's disease. Spatial mapping and in vitro assays demonstrated that thymic stromal lymphopoietin potently activated B cells, synergizing with classical stimuli to enhance proliferation. Activated B cells, in turn, secreted proinflammatory factors, such as, ICAM1 and CCL5, which induced epithelial apoptosis, suppressed proliferation, and disrupted tight junctions-effects that were amplified by thymic stromal lymphopoietin costimulation. Activated B cells and epithelial dysfunction were conserved in Hirschsprung-associated enterocolitis (Ednrb-/-) mouse models. Coculture and ex vivo organoid experiments confirmed that thymic stromal lymphopoietin-activated B cells directly destabilized epithelial homeostasis; crucially, baicalein treatment rescued epithelial proliferation, attenuated apoptosis, and reduced inflammation-associated gene expression.
CONCLUSIONS: Our study reveals a novel pathogenic mechanism whereby thymic stromal lymphopoietin instigates pathogenic B-cell hyperactivation, thereby disrupting epithelial integrity and increasing susceptibility to Hirschsprung-associated enterocolitis. Inhibition of thymic stromal lymphopoietin signaling with baicalein ameliorates epithelial injury, highlighting this axis as a promising therapeutic target for Hirschsprung-associated enterocolitis prevention in patients with Hirschsprung's disease.
METHODS: Integrated single-cell RNA sequencing, spatial transcriptomics, bulk RNA sequencing, and proteomics were performed using human Hirschsprung's disease tissues. Validation was conducted using murine Hirschsprung-associated enterocolitis (Ednrb-/-) models, flow cytometry, multiplex immunohistochemistry, in vitro B-cell stimulation, epithelial coculture, rescue experiments with the thymic stromal lymphopoietin inhibitor baicalein, and ex vivo intestinal organoid assays.
RESULTS: We identified significant expansion and hyperactivation of B cells that colocalized with epithelial barrier defects in Hirschsprung's disease segments. Multiomics analysis revealed an activated phenotype in these naive and memory B cells, characterized by the upregulation of B lymphocyte kinase, B cell linker, and proliferating cell nuclear antigen, which may contribute to impaired epithelial homeostasis. Crucially, we identified profibrotic thymic stromal lymphopoietin+ fibroblasts enriched in Hirschsprung's disease. Spatial mapping and in vitro assays demonstrated that thymic stromal lymphopoietin potently activated B cells, synergizing with classical stimuli to enhance proliferation. Activated B cells, in turn, secreted proinflammatory factors, such as, ICAM1 and CCL5, which induced epithelial apoptosis, suppressed proliferation, and disrupted tight junctions-effects that were amplified by thymic stromal lymphopoietin costimulation. Activated B cells and epithelial dysfunction were conserved in Hirschsprung-associated enterocolitis (Ednrb-/-) mouse models. Coculture and ex vivo organoid experiments confirmed that thymic stromal lymphopoietin-activated B cells directly destabilized epithelial homeostasis; crucially, baicalein treatment rescued epithelial proliferation, attenuated apoptosis, and reduced inflammation-associated gene expression.
CONCLUSIONS: Our study reveals a novel pathogenic mechanism whereby thymic stromal lymphopoietin instigates pathogenic B-cell hyperactivation, thereby disrupting epithelial integrity and increasing susceptibility to Hirschsprung-associated enterocolitis. Inhibition of thymic stromal lymphopoietin signaling with baicalein ameliorates epithelial injury, highlighting this axis as a promising therapeutic target for Hirschsprung-associated enterocolitis prevention in patients with Hirschsprung's disease.