374 Inflamed Ulcerative Colitis Regions Associated to Mrgprx2-Mediated Mast Cell Degranulation and Cell Activation Modules, Defining a New Therapeutic Target

Chuang, Ling-shiang F.; Chen, Ernie; Giri, Mamta; Villaverde, Nicole; Hsu, Nai-yun; Sabic, Ksenija; Joshowitz, Sari; Gettler, Kyle; Nayar, Shikha; Chen, Zhi; Alter, Isaac L.; Chasteau, Colleen; Korie, Ujunwa; Dzedzik, Siarhei; Thin, Tin Htwe; Jain, Aayushee; Moscati, Arden; Bongers, Gerold; Duerr, Richard H.; Silverberg, Mark S.; Brant, Steven R.; Rioux, John D.; Peter, Inga; Schumm, L. Philip; Haritunians, Talin; McGovern, Dermot; Itan, Yuval; Cho, Judy H.

doi:10.1016/s0016-5085(21)00921-5

Gastroenterology

2021

DOI: 10.1016/s0016-5085(21)00921-5

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374 Inflamed Ulcerative Colitis Regions Associated to Mrgprx2-Mediated Mast Cell Degranulation and Cell Activation Modules, Defining a New Therapeutic Target

Ling-shiang F. Chuang¹,

Ernie Chen²,

Mamta Giri³

et al.

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2022

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NOX1 is essential for TNFα-induced intestinal epithelial ROS secretion and inhibits M cell signatures

Hsu

Nayar

Gettler

et al. 2022

Gut

Self Cite

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ObjectiveLoss-of-function mutations in genes generating reactive oxygen species (ROS), such as NOX1, are associated with IBD. Mechanisms whereby loss of ROS drive IBD are incompletely defined.DesignROS measurements and single-cell transcriptomics were performed on colonoids stratified by NOX1 genotype and TNFα stimulation. Clustering of epithelial cells from human UC (inflamed and uninflamed) scRNASeq was performed. Validation of M cell induction was performed by immunohistochemistry using UEA1 (ulex europaeus agglutin-1 lectin) and in vivo with DSS injury.ResultsTNFα induces ROS production more in NOX1-WT versus NOX1-deficient murine colonoids under a range of Wnt-mediated and Notch-mediated conditions. scRNASeq from inflamed and uninflamed human colitis versus TNFα stimulated, in vitro colonoids defines substantially shared, induced transcription factors; NOX1-deficient colonoids express substantially lower levels of STAT3 (signal transducer and activator of transcription 3), CEBPD (CCAAT enhancer-binding protein delta), DNMT1 (DNA methyltransferase) and HIF1A (hypoxia-inducible factor) baseline. Subclustering unexpectedly showed marked TNFα-mediated induction of M cells (sentinel cells overlying lymphoid aggregates) in NOX1-deficient colonoids. M cell induction by UEA1 staining is rescued with H2O2 and paraquat, defining extra- and intracellular ROS roles in maintenance of LGR5+ stem cells. DSS injury demonstrated GP2 (glycoprotein-2), basal lymphoplasmacytosis and UEA1 induction in NOX1-deficiency. Principal components analyses of M cell genes and decreased DNMT1 RNA velocity correlate with UC inflammation.ConclusionsNOX1 deficiency plus TNFα stimulation contribute to colitis through dysregulation of the stem cell niche and altered cell differentiation, enhancing basal lymphoplasmacytosis. Our findings prioritise ROS modulation for future therapies.

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NOX1 is essential for TNFα-induced intestinal epithelial ROS secretion and inhibits M cell signatures

Hsu

Nayar

Gettler

et al. 2022

Gut

Self Cite

View full text Add to dashboard Cite

show abstract

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374 Inflamed Ulcerative Colitis Regions Associated to Mrgprx2-Mediated Mast Cell Degranulation and Cell Activation Modules, Defining a New Therapeutic Target

Cited by 1 publication

References 36 publications

NOX1 is essential for TNFα-induced intestinal epithelial ROS secretion and inhibits M cell signatures

NOX1 is essential for TNFα-induced intestinal epithelial ROS secretion and inhibits M cell signatures

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