GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology

Creators: Earley, Zachary M.; Lisicka, Wioletta; Sifakis, Joseph J.; Aguirre-Gamboa, Raúl; Kowalczyk, Anita; Barlow, Jacob T.; Shaw, Dustin G.; Discepolo, Valentina; Tan, Ineke L.; Gona, Saideep; Ernest, Jordan D.; Matzinger, Polly; Barreiro, Luis B.; Morgun, Andrey; Bendelac, Albert; Ismagilov, Rustem F.; Shulzhenko, Natalia; Riesenfeld, Samantha J.; Jabri, Bana

Abstract

There is growing recognition that regionalization of bacterial colonization and immunity along the intestinal tract has an important role in health and disease. Yet, the mechanisms underlying intestinal regionalization and its dysregulation in disease are not well understood. This study found that regional epithelial expression of the transcription factor GATA4 controls bacterial colonization and inflammatory tissue immunity in the proximal small intestine by regulating retinol metabolism and luminal IgA. Furthermore, in mice without jejunal GATA4 expression, the commensal segmented filamentous bacteria promoted pathogenic inflammatory immune responses that disrupted barrier function and increased mortality upon Citrobacter rodentium infection. In celiac disease patients, low GATA4 expression was associated with metabolic alterations, mucosal Actinobacillus, and increased IL-17 immunity. Taken together, these results reveal broad impacts of GATA4-regulated intestinal regionalization on bacterial colonization and tissue immunity, highlighting an elaborate interdependence of intestinal metabolism, immunity, and microbiota in homeostasis and disease.

Additional Information

© 2022 Elsevier. We would like to thank the patients and their family members, as well as the University of Chicago Celiac Disease Center, for supporting our research. We would like to thank Drs. Sonia Kupfer, Carol Semrad, Ritu Verma, Hilary Jericho, and Ian Wilson from the Celiac Disease Center for consenting and recruiting patients. We would like to thank Joaquín Sanz Remón for his help with the general transcriptional analysis of celiac disease and control patient biopsies. We thank Drs. Kenya Honda and Gabriel Nuñez for providing rat SFB and ΔEAE C. rodentium, respectively. We thank Ivaylo Ivanov for providing SFB TCR transgenic mice and for helpful discussions. We thank Steven Erickson from Dr. Albert Bendelac's lab for generating IgA- and Jh-deficient mice using CRISPR-Cas technologies based on previously published mouse models.24,55 We thank Betty Theriault, Kristin Kolar, and the entire Gnotobiotic Research Animal Facility at the University of Chicago for their help with the experiments involving gnotobiotic mice. We thank Yimei Chen and Tera Lavoie of the Advanced Electron Microscopy Core at University of Chicago for their help with transmission electron microscopy. We thank the Human Tissue Resource Center, the Integrated Light Microscopy Core Facility, Flow Cytometry Facility, and the Genomics Facility at the University of Chicago for their technical support. We thank Toufic Mayassi and Cezary Ciszewski for the thoughtful discussions and insightful comments. Finally, we thank Valerie Abadie for a critical reading of the manuscript and help with the graphical abstract. This work was supported by the National Institutes of Health via T32 AI007090 to Z.M.E., T32 GM007281 to D.G.S., U01AI109695 to A.M., U01 AI125250 to A.B., R01 AI144094 to A.B., R01DK103761 to N.S., R01 DK067180 to B.J., and the Digestive Diseases Research Core Center C-IID P30 DK42086 at the University of Chicago to B.J. Author contributions: Z.M.E. and B.J. conceived the study and designed the experiments. S.J.R. designed and oversaw computational analysis of the RNA-seq data with input from Z.M.E., B.J., J.J.S., and R.A.-G. Based on their previously published work and studies performed in gnotobiotic mice, N.S., A.M., and P.M. put forward the concept that absence of GATA4 in epithelial cells was driving inflammatory immune responses in the jejunum in a microbiota-dependent manner. Z.M.E., W.L., A.K., D.G.S., J.D.E., and J.T.B. performed the experiments. Z.M.E., W.L., J.J.S, R.A.-G., J.T.B., and S.J.R. analyzed and interpreted the data. J.J.S. performed computational analysis of mouse RNA-seq data, and R.A.-G. performed computational analysis of human RNA-seq data. J.T.B. performed the 16S sequencing and analysis. D.G.S. and V.D. created the RNA-seq libraries, and S.G. performed the DNA alignments. P.M. supervised an initial microarray transcriptional analysis. I.L.T contributed to and L.B.B. supervised RNA-seq analysis of human celiac disease patients. R.F.I. supervised the 16S analysis. A.B. supervised the IgA experiments. Z.M.E., S.J.R., and B.J. wrote the manuscript. W.L., J.J.S, J.T.B., R.F.I., A.M., N.S., and A.B. edited the manuscript. R.F.I., A.M., A.B., N.S., and B.J. acquired funds to support the work, and B.J. directed the study. Data and code availability. All the data supporting the findings of the article are available within the main text or supplementary information. The published article includes datasets generated during this study. Original RNA-seq data has been deposited in GEO: GSE205743. Original 16S rRNA sequencing datasets analyzed in this study are available at the NCBI BioProject: PRJNA797871. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. Original code for analyzing these datasets have been deposited in Zenodo and is publicly available. DOIs are listed in the key resources table. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.

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Resource type: Journal Article
Publisher: Cell Press
Published in: Immunity, 56(1), 43-57.e10, ISSN: 1074-7613.