长链非编码RNA对肠道巨噬细胞极化及免疫功能的调控

Intestinal macrophages are the main participants in intestinal mucosal immunity and play a crucial role in protecting the body from foreign pathogens and establishing immune tolerance in the gut. However, the exact mechanism of macrophage polarization in intestinal tissue remains unclear. Our previous study found that n-butyric acid can induce the expression of lnc-17Rik in macrophages. Therefore, the high expression of lnc-17Rik activates the transcriptional activity of macrophage polarization factor, which may be a new mechanism of n-butyric acid regulating macrophage polarization toward M2. To confirm this hypothesis, we intend to study 1）the regulatory effect of n-butyric acid on the expression of lnc-17Rik and its molecular mechanism；2）The regulatory role of lnc-17Rik on macrophage polarization and immune function; 3）The molecular mechanism of lnc-17Rik regulating macrophage polarization; 4）The effect of M6A methylation modification on the regulatory function of lnc-17Rik；5）The differential expression of lnc-17Rik in tumor tissue/Paracancerous tissue of colon cancer patients. By studying the molecular mechanism of lnc-17Rik in the polarization and functional regulation of intestinal macrophages, this study will explore the important role of epigenetic modification in the balance of intestinal immune system, so as to provide novel biomarkers or new drug development targets for the treatment of intestinal mucosal immune diseases.

肠道巨噬细胞是肠黏膜免疫的主要参与者，在保护机体免受病原体侵害及在肠道中建立免疫耐受方面发挥重要作用。然而巨噬细胞在肠道组织中极化的机制尚不清楚。前期研究发现正丁酸能够诱导巨噬细胞lnc-17Rik的表达，因此lnc-17Rik的高表达并激活巨噬细胞极化因子的转录活性，可能是正丁酸调控巨噬细胞向M2方向极化的新机制。为证实该假说拟开展研究1）正丁酸对lnc-17Rik的调控及分子机制；2）lnc-17Rik对巨噬细胞极化及免疫功能的调控作用；3）lnc-17Rik调控巨噬细胞极化的分子机制；4）M6A甲基化修饰对lnc-17Rik调控功能的影响；5）lnc-17Rik在结肠癌患者肿瘤组织/癌旁组织中的表达差异。本课题将通过研究lnc-17Rik对肠道巨噬细胞极化及功能调控的分子机制，探索表观遗传修饰在肠道免疫系统平衡中的重要作用，以期为肠黏膜免疫疾病的治疗提供新的生物标志物或新药研究靶点。

巨噬细胞主要分为两个亚群，它们在生理和病理条件下发挥着不同的作用。这些细胞的分化可能受到转录因子的调控。然而，目前尚不清楚如何调节这些转录因子来影响这些细胞的分化。在这里，我们发现lncLy6C，一种新的超保守lncRNA，促进Ly6C high炎性单核细胞向Ly6C low/neg驻留巨噬细胞的分化。我们证明，肠道微生物群代谢产物丁酸盐上调lncLy6C的表达。LncLy6C缺陷小鼠的Ly6C high促炎单核细胞显著增加，Ly6C neg驻留巨噬细胞减少。LncLy6C不仅与转录因子C/EBPβ结合，还与H3K4me3的多种赖氨酸甲基转移酶结合，以特异性地促进C/EBPβ和H3K4me3标记在Nr4A1启动子区的富集，这可以促进Ly6Chigh进入Ly6Cneg巨噬细胞。因此，lncLy6C导致Nr4A1的上调，以促进Ly6Chigh炎性单核细胞分化为Ly6Cint/neg驻留巨噬细胞。对预防结肠炎的发生和发展具有重要的生理和临床意义。