Macrophages are mainly divided into two populations, which play a different role in physiological and pathological conditions. The differentiation of these cells may be regulated by transcription factors. However, it is unclear how to modulate these transcription factors to affect differentiation of these cells. Here, we found that lncLy6C, a novel ultraconserved lncRNA, promotes differentiation of Ly6C^high inflammatory monocytes into Ly6C^low/neg resident macrophages. We demonstrate that gut microbiota metabolites butyrate upregulates the expression of lncLy6C. LncLy6C deficient mice had markedly increased Ly6C^high pro-inflammatory monocytes and reduced Ly6C^neg resident macrophages. LncLy6C not only bound with transcription factor C/EBPβ but also bound with multiple lysine methyltransferases of H3K4me3 to specifically promote the enrichment of C/EBPβ and H3K4me3 marks on the promoter region of Nr4A1, which can promote Ly6C^high into Ly6C^neg macrophages. As a result, lncLy6C causes the upregulation of Nr4A1 to promote Ly6C^high inflammatory monocytes to differentiate into Ly6C^int/neg resident macrophages.

巨噬细胞主要分为两个种群，它们在生理和病理状况中起着不同的作用。这些细胞的分化可能受转录因子调控。但是，尚不清楚如何调节这些转录因子以影响这些细胞的分化。在这里，我们发现lncLy6C，一种新型的超保守lncRNA，可促进Ly6C^高炎症单核细胞分化为Ly6C^低/阴性常驻巨噬细胞。我们证明肠道菌群代谢产物丁酸上调lncLy6C的表达。LncLy6C缺陷小鼠的Ly6C^高促炎性单核细胞明显增加，而Ly6C ^neg减少常驻巨噬细胞。LncLy6C不仅与转录因子C /EBPβ结合，而且与H3K4me3的多个赖氨酸甲基转移酶结合，以特异性促进Nr4A1启动子区域上C /EBPβ和H3K4me3标记的富集，从而可以将Ly6C^高度提升为Ly6C ^neg巨噬细胞。结果，lncLy6C导致Nr4A1上调，从而促进Ly6C^高炎症单核细胞分化为Ly6C ^{int / neg}驻留巨噬细胞。