LncRNA lncLy6C induced by microbiota metabolite butyrate promotes differentiation of Ly6Chigh to Ly6Cint/neg macrophages through lncLy6C/C/EBPβ/Nr4A1 axis

Abstract

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 Ly6Chigh inflammatory monocytes into Ly6Clow/neg resident macrophages. We demonstrate that gut microbiota metabolites butyrate upregulates the expression of lncLy6C. LncLy6C deficient mice had markedly increased Ly6Chigh pro-inflammatory monocytes and reduced Ly6Cneg 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 Ly6Chigh into Ly6Cneg macrophages. As a result, lncLy6C causes the upregulation of Nr4A1 to promote Ly6Chigh inflammatory monocytes to differentiate into Ly6Cint/neg resident macrophages.

The Interplay between the Gut Microbiome and the Immune System in the Context of Infectious Diseases throughout Life and the Role of Nutrition in Optimizing Treatment Strategies

“…The ability of signaling molecules released by the microbiota to enter the circulation also allows resident bacteria in the gut to already modulate the immune system during immune cell development during hematopoiesis and, in that way, influence the response to infection [ 1 , 47 ]. Indeed, the SCFA butyrate was shown to promote the differentiation of bone marrow monocytes from an inflammatory phenotype to a more tolerogenic phenotype [ 48 ]. Bone marrow cells also express a variety of PRRs and are susceptible to circulating MAMPs with differential effects dictated by PRR expression and MAMP availability [ 49 ].…”

Effects of Long Non-Coding RNAs Induced by the Gut Microbiome on Regulating the Development of Colorectal Cancer

“…The underlying processes by which the gut microbiome contributes to CRC have been the subject of various research, which have shown that numerous pathogenic bacteria and metabolites of the gut microbiome can affect the progression of CRC by controlling the expression of lncRNAs [ 17 , 36 , 37 ]. By upregulating LINC00152, a gene associated with intestinal inflammation, cancer cell migration, and invasion, Wang et al discovered that Salmonella typhimurium infection affected the lncRNAs expression in intestinal epithelial cells [ 36 ].…”

“…According to Chen et al, Fusobacterium nucleatum infection upregulates the lncRNAs Keratin7-antisense (KRT7-AS) and Keratin7 (KRT7) by triggering the NF-κB pathway to promote CRC metastasis [ 17 ]. Conversely, the gut microbiome metabolite butyrate-induced lncRNA LncLy6C suppressed intestinal inflammation, thus lowering the risk of CRC, according to the research by Gao et al [ 37 ]. Therefore, it is reasonable to assume that gut microbiome disorders can influence CRC development via mediating lncRNAs.…”

“…In addition to the gut microbiome, which can directly regulate lncRNAs to influence CRC progression, the gut microbiome metabolite butyrate can likewise control the expression of lncRNAs and thus play a significant role in CRC development [ 37 ]. Butyrate is a major metabolite produced by the fermentation of dietary fiber bacteria in the gastrointestinal tract.…”

The Role of the Gut Microbiome in Pathogenesis, Biology, and Treatment of Plasma Cell Dyscrasias

“…The ability of microbes to release signaling molecules into the bloodstream can modulate the host's response to infections via the regulation of immune cell development (21). For instance, butyrate secreted by bacteria promotes the differentiation of monocytes in the bone marrow to a tolerogenic phenotype (22). Moreover, it was recently showed that some bacterial species could decrease the level of corticosterone in the blood which could improve the function of the immune system during the infection (23).…”