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

Abstract

RUNX3 is one of three mammalian Runt-domain transcription factors (TFs) that regulate gene expression in several types of immune cells. Runx3-deficiency in mice is associated with a multitude of defects in the adaptive and innate immunity systems, including the development of early onset colitis. Our study reveals that conditional deletion of Runx3 specifically in mononuclear phagocytes (MNP) (MNP Runx3-/-) but not in T cells, recapitulates the early onset spontaneous colitis seen in Runx3 -/mice.We show that Runx3 is expressed in colonic MNP, including resident macrophages (RM) and the dendritic cell cDC2 subsets and its loss results in impaired differentiation/maturation of both cell types. At the transcriptome level, loss of Runx3 in RM and cDC2 was associated with upregulation of pro-inflammatory genes similar to those in the early onset IBD murine model of RM Il10r-/-. The impaired RM maturation in the absence of Runx3 was associated with a marked decrease in expression of antiinflammatory and TGFb-regulated genes. Similarly, the decreased expression of b-

Waiting in the wings: RUNX3 reveals hidden depths of immune regulation with potential implications for inflammatory bowel disease

“…As colonic CD11b + DCs present high expression levels of Runx3 , conditional knockout of Runx3 especially affects this immune cell subset. Consequently, Runx3‐deficient CD11b + DCs are characterized by reduced expression of TGF‐β–regulated anti‐inflammatory genes 91 . The latest studies investigated the Runx3‐TGF‐β1 inflammatory pathway 89,90,92 .…”

“…Runx3‐deficient macrophages are characterized by downregulated anti‐inflammatory genes and disturbed repression of proinflammatory genes through the Runx3/Stat3 axis 91 . Balance of IL‐22 and its antagonist, IL‐22 binding protein (Il22ra), is of utmost importance in the regulation of inflammation 91 . Intestinal macrophages reduce their expression of Il22ra2 in the absence of Runx3.…”

“…Decreased expression of Il22ra2 increases response to IL‐22. This induces an inflammatory response in the colonic epithelium and thus leads to colitis 91 . Li et al studied the regulatory mechanisms of macrophage polarization 108 .…”

“…Transcriptome analysis in immune cells from normal and Runx3‐deficient mice coupled with Runx3 ChiP‐seq identified hundreds of Runx3 target genes in CD8 + T, natural killer and dendritic cells, as well as intestinal macrophages 91,112 . The human homologs of many of these Runx3 target genes, and RUNX3 itself, were found to be associated with IBD 91,112 . Marbach et al 6 used enhancers and promoters previously validated in FANTOM5 project to investigate immune‐related transcription factor networks.…”

“…89,90 A mouse model of early-onset colitis showed that Runx3-deficient DCs (and macrophages), rather than T cells lacking Runx3, cause spontaneous inflammation in the gut. 91 Functional Runx3 maintains mononuclear phagocyte maturation and anti-inflammatory functions. 91 As colonic CD11b + DCs present high expression levels of Runx3, conditional knockout of Runx3 especially affects this immune cell subset.…”