Human lncRNA, hLinfRNA7 (IDO1-AS) Regulates Cytokine Expression, Tryptophan Catabolism, and Inflammatory Response in Macrophage

Noncoding RNAs are emerging players in cell signaling and diseases. Recently, we discovered a series of novel lncRNAs that are critical players in inflammation. Here, we demonstrate that hLinfRNA7, a long human noncoding inflammation-associated RNA 7 (also termed as IDO1-AS6.4) located on the antisense-strand of IDO1 (Indoleamine-2,3 -dioxygenase 1, a tryptophan catabolizing enzyme), plays critical roles in the regulation of inflammation and tryptophan (Trp) catabolism. Our studies demonstrated that hLinfRNA7 expression is induced in human THP1-derived macrophages under inflammation (LPS or IFNγ- stimulation) and is localized in the nucleus. hLinfRNA7 knockdown suppressed LPS-induced IL-6, IL-1β, and iNOS expression and reduced nitric oxide production. Interestingly, hLinfRNA7 knockdown also downregulated the inflammation-induced expression of IDO1 as well as the tryptophan catabolite kynurenine level in macrophages, suggesting critical roles of hLinfRNA7 in inflammation, cytokine regulation, and Trp-catabolism. Furthermore, IDO1 also regulate hLinfRNA7 expression, suggesting their interplay in inflammation and Trp-catabolism. hLinfRNA7 also modulates NF-κB signaling and interacts with an RNA-binding protein, YBX1, which also regulates cytokines, IDO1, hLinfRNA7, and Trp-catabolism under inflammation. Our study demonstrates lncRNA hLinfRNA7 is a novel regulator of inflammation and tryptophan catabolism. By delineating an hLinfRNA7-YBX1-IDO1 axis, our study expands lncRNA roles in immune-metabolic control and inflammatory disease.