1. Runx3 prevents spontaneous colitis by directing the differentiation of anti-inflammatory mononuclear phagocytes
- Author
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Yoram Groner, Dalia Goldenberg, Shay Hantisteanu, Yosef Dicken, Dena Leshkowitz, Joseph Lotem, Ori Brenner, Ditsa Levanon, and Varda Negreanu
- Subjects
0301 basic medicine ,Cellular differentiation ,Gene Expression ,Pathology and Laboratory Medicine ,Monocytes ,Immune tolerance ,Transcriptome ,White Blood Cells ,Mice ,0302 clinical medicine ,Spectrum Analysis Techniques ,Animal Cells ,Transforming Growth Factor beta ,Medicine and Health Sciences ,Receptors, Interleukin-10 ,Immune Response ,Mononuclear Phagocyte System ,beta Catenin ,Multidisciplinary ,T Cells ,Cell Differentiation ,Colitis ,Flow Cytometry ,Up-Regulation ,Spectrophotometry ,Medicine ,Cytophotometry ,Signal transduction ,Anatomy ,Cellular Types ,Research Article ,Signal Transduction ,Colon ,Science ,Immune Cells ,Immunology ,Gastroenterology and Hepatology ,Biology ,Research and Analysis Methods ,03 medical and health sciences ,Immune system ,Signs and Symptoms ,Diagnostic Medicine ,medicine ,Genetics ,Animals ,Humans ,Transcription factor ,Inflammation ,Blood Cells ,Inflammatory Bowel Disease ,Biology and Life Sciences ,Dendritic cell ,Cell Biology ,medicine.disease ,digestive system diseases ,Gastrointestinal Tract ,Disease Models, Animal ,030104 developmental biology ,Core Binding Factor Alpha 3 Subunit ,Digestive System ,030215 immunology - 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.
- Published
- 2020