Long Noncoding RNA AW112010 Promotes the Differentiation of Inflammatory T Cells by Suppressing IL-10 Expression through Histone Demethylation

Abstract

Long noncoding RNAs (lncRNAs) have been demonstrated to play important regulatory roles in gene expression, from histone modification to protein stability. However, the functions of most identified lncRNAs are not known. In this study, we investigated the role of an lncRNA called AW112010. The expression of AW112010 was significantly increased in CD4 + T cells from C57BL/6J mice activated in vivo with myelin oligodendrocyte glycoprotein, Staphylococcal enterotoxin B, or in vitro with anti-CD3 anti-CD28 mAbs, thereby demonstrating that activation of T cells leads to induction of AW112010. In contrast, anti-inflammatory cannabinoids such as cannabidiol or d-9-tetrahydrocannabinol decreased the expression of AW112010 in T cells. Interestingly, the expression of AW112010 was high in in vitro-polarized Th1 and Th17 cells but low in Th2 cells, suggesting that this lncRNA may regulate inflammation. To identify genes that might be regulated by AW112010, we used chromatin isolation by RNA purification, followed by sequencing. This approach demonstrated that AW112010 regulated the transcription of IL-10. Additionally, the level of IL-10 in activated T cells was low when the expression of AW112010 was increased. Use of small interfering RNA to knock down AW112010 expression in activated T cells led to increased IL-10 expression and a decrease in the expression of IFN-g. Further studies showed that AW112010 interacted with histone demethylase KDM5A, which led to decreased H3K4 methylation in IL-10 gene locus. Together, these studies demonstrate that lncRNA AW112010 promotes the differentiation of inflammatory T cells by suppressing IL-10 expression through histone demethylation.

Epigenetic Regulation of Cannabinoid-Mediated Attenuation of Inflammation and Its Impact on the Use of Cannabinoids to Treat Autoimmune Diseases

“…Long noncoding RNAs (lncRNAs) have been shown to play a critical role in gene expression, from histone modification to stability of proteins. Recent studies from our lab showed that an lncRNA called AW112010 was significantly induced in activated CD4+ T cells and CBD or THC could decrease the expression of AW112010 in T cells [ 101 ]. Additional studies showed that lncRNA AW112010 suppressed IL-10, thereby promoting the differentiation of inflammatory T cells through histone demethylation [ 101 ].…”

“…Recent studies from our lab showed that an lncRNA called AW112010 was significantly induced in activated CD4+ T cells and CBD or THC could decrease the expression of AW112010 in T cells [ 101 ]. Additional studies showed that lncRNA AW112010 suppressed IL-10, thereby promoting the differentiation of inflammatory T cells through histone demethylation [ 101 ]. Thus, cannabinoids could induce immunosuppressive cytokines such as IL-10 through downregulation of lncRNA AW112010.…”

Integrative Analysis of Spatial Transcriptome with Single-cell Transcriptome and Single-cell Epigenome in Mouse Lungs after Immunization

“…AW112010, a top DE gene up-regulated in the airways upon re-challenge, was highly expressed in the airways of the re-challenged mouse (Figures 5B). AW112010 has also been reported capable of promoting the differentiation of inflammatory T cells 16 . Cbr2, a top DE gene down-regulated in the airways upon re-challenge, was highly expressed in the airways of the immunized mouse (Figures 5C), and may function in the metabolism of endogenous carbonyl compounds 17 and alveolar epithelial cell plasticity 18 .…”

LncRNA-ENST00000421645 Upregulates Kank1 to Inhibit IFN-γ Expression and Promote T Cell Apoptosis in Neurosyphilis

“…For example, after Toxoplasma gondii infection, non-shat022487 inhibits IL-12, tumor necrosis factor-α (TNF-α) and IFN-γ expression by downregulating the expression of the immune-activating molecule unc93b1 in human macrophages ( Liu et al, 2018 ), contributing to the establishment of chronic Toxoplasma infection. In staphylococcal enterotoxin B-activated CD4 + T cells of C57BL/6J mice, the long non-coding RNA (lncRNA) AW112010 inhibits IL-10 expression through histone demethylation and promotes the differentiation of inflammatory T cells ( Yang et al, 2020 ). During Mycobacterium tuberculosis infection, lncRNA-CD244 directly interacts with the polycomb repressive complexes(PRC2) subunit enhancer of zeste homolog 2(EZH2), which leads to histone H3 lysine (K) 27 methylation and confers a stronger inhibitory chromatin state at IFN-γ or TNF-α loci ( Wang et al, 2015 ).…”