GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology

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

doi:10.1016/j.immuni.2022.12.009

GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology

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

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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.

Original language	English
Pages (from-to)	43-57.e10
Journal	Immunity
Volume	56
Issue number	1
DOIs	https://doi.org/10.1016/j.immuni.2022.12.009
State	Published - 10 Jan 2023
Externally published	Yes

Keywords

GATA4
IgA
bacterial colonization
celiac disease
immunopathology
infection
intestinal epithelial cells
intestinal regionalization
retinoic acid
segmented filamentous bacteria

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10.1016/j.immuni.2022.12.009

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Earley, Z. M., Lisicka, W., Sifakis, J. J., Aguirre-Gamboa, R., Kowalczyk, A., Barlow, J. T., Shaw, D. G., Discepolo, V., Tan, I. L., Gona, S., Ernest, J. D., Matzinger, P., Barreiro, L. B., Morgun, A., Bendelac, A., Ismagilov, R. F., Shulzhenko, N., Riesenfeld, S. J., & Jabri, B. (2023). GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology. Immunity, 56(1), 43-57.e10. https://doi.org/10.1016/j.immuni.2022.12.009

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title = "GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology",

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.",

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year = "2023",

month = jan,

day = "10",

doi = "10.1016/j.immuni.2022.12.009",

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Earley, ZM, Lisicka, W, Sifakis, JJ, Aguirre-Gamboa, R, Kowalczyk, A, Barlow, JT, Shaw, DG, Discepolo, V, Tan, IL, Gona, S, Ernest, JD, Matzinger, P, Barreiro, LB, Morgun, A, Bendelac, A, Ismagilov, RF, Shulzhenko, N, Riesenfeld, SJ & Jabri, B 2023, 'GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology', Immunity, vol. 56, no. 1, pp. 43-57.e10. https://doi.org/10.1016/j.immuni.2022.12.009

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T1 - GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology

AU - Earley, Zachary M.

AU - Lisicka, Wioletta

AU - Sifakis, Joseph J.

AU - Aguirre-Gamboa, Raúl

AU - Kowalczyk, Anita

AU - Barlow, Jacob T.

AU - Shaw, Dustin G.

AU - Discepolo, Valentina

AU - Tan, Ineke L.

AU - Gona, Saideep

AU - Ernest, Jordan D.

AU - Matzinger, Polly

AU - Barreiro, Luis B.

AU - Morgun, Andrey

AU - Bendelac, Albert

AU - Ismagilov, Rustem F.

AU - Shulzhenko, Natalia

AU - Riesenfeld, Samantha J.

AU - Jabri, Bana

PY - 2023/1/10

Y1 - 2023/1/10

N2 - 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.

AB - 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.

KW - GATA4

KW - IgA

KW - bacterial colonization

KW - celiac disease

KW - immunopathology

KW - infection

KW - intestinal epithelial cells

KW - intestinal regionalization

KW - retinoic acid

KW - segmented filamentous bacteria

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U2 - 10.1016/j.immuni.2022.12.009

DO - 10.1016/j.immuni.2022.12.009

M3 - Article

C2 - 36630917

AN - SCOPUS:85145717411

SN - 1074-7613

VL - 56

SP - 43-57.e10

JO - Immunity

JF - Immunity

IS - 1

ER -

GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology

Abstract

Keywords

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