Cytokine Responsive Networks in Human Colonic Epithelial Organoids Unveil a Molecular Classification of Inflammatory Bowel Disease

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2022 Sep 28

PMID 36170836

Authors

Polychronis Pavlidis

Anastasia Tsakmaki

Agatha Treveil

Katherine Li

Domenico Cozzetto

Feifei Yang

Umar Niazi

Bu Hussain Hayee

Mansoor Saqi

Joshua Friedman

Tamas Korcsmaros

Gavin Bewick

Nick Powell

Affiliations

Soon will be listed here.

Abstract

Interactions between the epithelium and the immune system are critical in the pathogenesis of inflammatory bowel disease (IBD). In this study, we mapped the transcriptional landscape of human colonic epithelial organoids in response to different cytokines responsible for mediating canonical mucosal immune responses. By profiling the transcriptome of human colonic organoids treated with the canonical cytokines interferon gamma, interleukin-13, -17A, and tumor necrosis factor alpha with next-generation sequencing, we unveil shared and distinct regulation patterns of epithelial function by different cytokines. An integrative analysis of cytokine responses in diseased tissue from patients with IBD (n = 1,009) reveals a molecular classification of mucosal inflammation defined by gradients of cytokine-responsive transcriptional signatures. Our systems biology approach detected signaling bottlenecks in cytokine-responsive networks and highlighted their translational potential as theragnostic targets in intestinal inflammation.

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References

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

Sato T, Stange D, Ferrante M, Vries R, van Es J, van den Brink S . Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology. 2011; 141(5):1762-72. DOI: 10.1053/j.gastro.2011.07.050. View

Wehkamp J, Salzman N, Porter E, Nuding S, Weichenthal M, Petras R . Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natl Acad Sci U S A. 2005; 102(50):18129-34. PMC: 1306791. DOI: 10.1073/pnas.0505256102. View

Kramer A, Green J, Pollard Jr J, Tugendreich S . Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics. 2013; 30(4):523-30. PMC: 3928520. DOI: 10.1093/bioinformatics/btt703. View

Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I . Controlling the false discovery rate in behavior genetics research. Behav Brain Res. 2001; 125(1-2):279-84. DOI: 10.1016/s0166-4328(01)00297-2. View

Russell L, Garrett-Sinha L . Transcription factor Ets-1 in cytokine and chemokine gene regulation. Cytokine. 2010; 51(3):217-26. DOI: 10.1016/j.cyto.2010.03.006. View

Gerlach K, Hwang Y, Nikolaev A, Atreya R, Dornhoff H, Steiner S . TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat Immunol. 2014; 15(7):676-86. DOI: 10.1038/ni.2920. View

Hanzelmann S, Castelo R, Guinney J . GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013; 14:7. PMC: 3618321. DOI: 10.1186/1471-2105-14-7. View

de Lange K, Moutsianas L, Lee J, Lamb C, Luo Y, Kennedy N . Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet. 2017; 49(2):256-261. PMC: 5289481. DOI: 10.1038/ng.3760. View

10.

Yu G, He Q . ReactomePA: an R/Bioconductor package for reactome pathway analysis and visualization. Mol Biosyst. 2015; 12(2):477-9. DOI: 10.1039/c5mb00663e. View

11.

Cadwell K, Liu J, Brown S, Miyoshi H, Loh J, Lennerz J . A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008; 456(7219):259-63. PMC: 2695978. DOI: 10.1038/nature07416. View

12.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

13.

Monteleone G, Biancone L, Marasco R, Morrone G, Marasco O, Luzza F . Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology. 1997; 112(4):1169-78. DOI: 10.1016/s0016-5085(97)70128-8. View

14.

Arijs I, Li K, Toedter G, Quintens R, Van Lommel L, Van Steen K . Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis. Gut. 2009; 58(12):1612-9. DOI: 10.1136/gut.2009.178665. View

15.

Sato T, Vries R, Snippert H, van de Wetering M, Barker N, Stange D . Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009; 459(7244):262-5. DOI: 10.1038/nature07935. View

16.

Fuss I, Neurath M, Boirivant M, Klein J, de La Motte C, Strong S . Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996; 157(3):1261-70. View

17.

Feagan B, Sandborn W, Gasink C, Jacobstein D, Lang Y, Friedman J . Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med. 2016; 375(20):1946-1960. DOI: 10.1056/NEJMoa1602773. View

18.

Garrett W, Lord G, Punit S, Lugo-Villarino G, Mazmanian S, Ito S . Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell. 2007; 131(1):33-45. PMC: 2169385. DOI: 10.1016/j.cell.2007.08.017. View

19.

Park H, Li Z, Yang X, Chang S, Nurieva R, Wang Y . A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005; 6(11):1133-41. PMC: 1618871. DOI: 10.1038/ni1261. View

20.

Nanki K, Fujii M, Shimokawa M, Matano M, Nishikori S, Date S . Somatic inflammatory gene mutations in human ulcerative colitis epithelium. Nature. 2019; 577(7789):254-259. DOI: 10.1038/s41586-019-1844-5. View