Runx3 prevents spontaneous colitis by directing the differentiation of anti-inflammatory mononuclear phagocytes

Shay Hantisteanu; Yosef Dicken; Varda Negreanu; Dalia Goldenberg; Ori Brenner; Dena Leshkowitz; Joseph Lotem; Ditsa Levanon; Yoram Groner

doi:10.1371/journal.pone.0233044

Runx3 prevents spontaneous colitis by directing the differentiation of anti-inflammatory mononuclear phagocytes

Shay Hantisteanu, Yosef Dicken, Varda Negreanu, Dalia Goldenberg, Ori Brenner, Dena Leshkowitz, Joseph Lotem, Ditsa Levanon, Yoram Groner^*

^*Corresponding author for this work

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

16 Citations (Scopus)

Abstract

Mice deficient in the transcription factor Runx3 develop a multitude of immune system defects, including early onset colitis. This paper demonstrates that Runx3 is expressed in colonic mononuclear phagocytes (MNP), including resident macrophages (RM) and dendritic cell subsets (cDC2). Runx3 deletion in MNP causes early onset colitis due to their impaired maturation. Mechanistically, the resulting MNP subset imbalance leads to up-regulation of pro-inflammatory genes as occurs in IL10R-deficient RM. In addition, RM and cDC2 display a marked decrease in expression of anti-inflammatory/TGF β-regulated genes and β-catenin signaling associated genes, respectively. MNP transcriptome and ChIP-seq data analysis suggest that a significant fraction of genes affected by Runx3 loss are direct Runx3 targets. Collectively, Runx3 imposes intestinal immune tolerance by regulating maturation of colonic anti-inflammatory MNP, befitting the identification of RUNX3 as a genome-wide associated risk gene for various immune-related diseases in humans, including gastrointestinal tract diseases such as Crohn's disease and celiac.

Original language	English
Article number	e0233044
Number of pages	27
Journal	PLoS ONE
Volume	15
Issue number	5
DOIs	https://doi.org/10.1371/journal.pone.0233044
Publication status	Published - 26 May 2020

Funding

We thank Steffen Jung and Ehud Zigmond from the Weizmann Institute Department of Immunology for helpful discussions and for providing the D1 cell line and the Cx3cr1-Cre, Cx3cr1-GFP and CD45.1 mice; Aharon Nachshon from the Weizmann Institute Department of Molecular Genetics for help with statistical analysis; Ofira Higfa, Rafael Saka and Pavel Bell for assisting with animal husbandry; Sima Peretz for assistance in intravenous injections and Calanit Raanan for preparation of tissue sections and Shirely Horn Saban for help in gene expression data acquisition. This study was supported by grants from Israel Science Foundation individual grants to Yoram Groner. URL: http://isf.org.il. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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title = "Runx3 prevents spontaneous colitis by directing the differentiation of anti-inflammatory mononuclear phagocytes",

abstract = "Mice deficient in the transcription factor Runx3 develop a multitude of immune system defects, including early onset colitis. This paper demonstrates that Runx3 is expressed in colonic mononuclear phagocytes (MNP), including resident macrophages (RM) and dendritic cell subsets (cDC2). Runx3 deletion in MNP causes early onset colitis due to their impaired maturation. Mechanistically, the resulting MNP subset imbalance leads to up-regulation of pro-inflammatory genes as occurs in IL10R-deficient RM. In addition, RM and cDC2 display a marked decrease in expression of anti-inflammatory/TGF β-regulated genes and β-catenin signaling associated genes, respectively. MNP transcriptome and ChIP-seq data analysis suggest that a significant fraction of genes affected by Runx3 loss are direct Runx3 targets. Collectively, Runx3 imposes intestinal immune tolerance by regulating maturation of colonic anti-inflammatory MNP, befitting the identification of RUNX3 as a genome-wide associated risk gene for various immune-related diseases in humans, including gastrointestinal tract diseases such as Crohn's disease and celiac.",

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AU - Leshkowitz, Dena

AU - Lotem, Joseph

AU - Levanon, Ditsa

AU - Groner, Yoram

N1 - Publisher Copyright: © 2020 Hantisteanu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2020/5/26

Y1 - 2020/5/26

N2 - Mice deficient in the transcription factor Runx3 develop a multitude of immune system defects, including early onset colitis. This paper demonstrates that Runx3 is expressed in colonic mononuclear phagocytes (MNP), including resident macrophages (RM) and dendritic cell subsets (cDC2). Runx3 deletion in MNP causes early onset colitis due to their impaired maturation. Mechanistically, the resulting MNP subset imbalance leads to up-regulation of pro-inflammatory genes as occurs in IL10R-deficient RM. In addition, RM and cDC2 display a marked decrease in expression of anti-inflammatory/TGF β-regulated genes and β-catenin signaling associated genes, respectively. MNP transcriptome and ChIP-seq data analysis suggest that a significant fraction of genes affected by Runx3 loss are direct Runx3 targets. Collectively, Runx3 imposes intestinal immune tolerance by regulating maturation of colonic anti-inflammatory MNP, befitting the identification of RUNX3 as a genome-wide associated risk gene for various immune-related diseases in humans, including gastrointestinal tract diseases such as Crohn's disease and celiac.

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Runx3 prevents spontaneous colitis by directing the differentiation of anti-inflammatory mononuclear phagocytes

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