Butyrate-LncRNALy6C-RUNX3 axis determines gut resident macrophages by NR4A1 mediated ERK1/2/MAPK pathway

Gut resident macrophages play a critical role in maintaining gut homeostasis. These resident macrophages may come from peripheral blood inflammatory monocytes. However, the mechanism (s) for the differentiation of inflammatory monocytes into gut resident macrophages maintain to be further understood. We here found that transcription factor RUNX3 play a critical role in the process of inflammatory monocytes into resident macrophages. RUNX3flow/flowlyz2-Cre mice had decreased resident macrophages, increased ZFP36, which could cause degradation of cytokines and chemokines in the resident macrophages of colon tissues. RUNX3 could promote the expression of NR4A1, which could induce the differentiation of inflammatory monocytes into resident macrophages. Single cell population analyses found that ERK1/2/MAPK pathway played a critical role in NR4A1 mediated differentiation of gut resident macrophages. Notably, RUNX3 expression could be promoted by butyrate through lncRNALy6C. Interestingly, high levels of lncRNALy6C, RUNX3, NR4A1 and ZFP36 could be detected in the resident macrophages of healthy individuals. Thus, there exists a butyrate-LncRNA6C-RUNX3-NR4A1-REK1/2 MAPK axis to maintain gut homeostasis through increasing resident macrophages and promoting ZFP36 expression in the macrophages.