Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.
Veterinary Resources, The Weizmann Institute of Science, Rehovot, Israel.
PLoS One. 2020 May 26;15(5):e0233044. doi: 10.1371/journal.pone.0233044. eCollection 2020.
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.
转录因子 Runx3 缺失的小鼠会出现多种免疫系统缺陷，包括结肠炎的早期发病。本文证明 Runx3 在结肠单核吞噬细胞（MNP）中表达，包括固有巨噬细胞（RM）和树突状细胞亚群（cDC2）。MNP 中的 Runx3 缺失导致结肠炎的早期发病，原因是其成熟受损。从机制上讲，由此产生的 MNP 亚群失衡会导致促炎基因的上调，就像 IL10R 缺陷型 RM 中发生的那样。此外，RM 和 cDC2 分别显示抗炎/TGFβ调节基因和β-连环蛋白信号相关基因的表达显著下降。MNP 转录组和 ChIP-seq 数据分析表明，受 Runx3 缺失影响的基因中有很大一部分是直接的 Runx3 靶基因。总的来说，Runx3 通过调节结肠抗炎性 MNP 的成熟来施加肠道免疫耐受，这符合 RUNX3 被鉴定为人类各种与免疫相关疾病（包括胃肠道疾病，如克罗恩病和乳糜泻）的全基因组关联风险基因。
