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Palmitic acid induced lncRNA PARAIL regulates inflammation in human monocytes and macrophages

Elevated circulating levels of long chain saturated fatty acids such as Palmitic acid (PA) enhances inflammation, metabolic disorders like diabetes and associated complications. Accumulated evidence shows that long non‐coding RNAs (lncRNAs) play key roles in the regulation of inflammation, however, their role in PA‐induced inflammation in monocytes/macrophages is not well known. Strand‐specific RNA‐seq was performed to identify PA‐induced lncRNAs in CD14+ human monocytes. The RNA‐seq results showed that 2624 transcripts including lncRNAs were differentially expressed in PA treated CD14+ human monocytes. Interestingly, PA significantly induced genes associated with inflammatory phenotype. Here we studied a PA‐induced lncRNA RP11‐37B2 located adjacent to RIPK2, which we designated as PA‐ regulated anti‐ inflammatory lncRNA (PARAIL). PARAIL was induced by PA in a time and dose dependent manner with optimal induction by 200 μM PA at 24 h in THP1 monocytes differentiated into macrophages. Analysis of publicly available datasets showed that PARAIL is also upregulated by lipopolysaccharide (LPS) and bacterial infection in human monocytes and macrophages. PARAIL promoter showed binding motif for NF‐kB, and the NF‐κB inhibitor BAY 11‐7082 significantly inhibited PA‐induced expression of PARAIL. Furthermore, PARAIL knockdown with GapmeR antisense oligonucleotides increased pro‐inflammatory cytokines and suppressed anti‐inflammatory chemokines in THP‐1 macrophages. In addition, mouse orthologous Parail was down regulated in peritoneal macrophages from diabetic db/db mice and bone marrow derived macrophages from Apoe−/− mice, a model of accelerated atherosclerosis. Together, these results show that PA‐induces lncRNA PARAIL in human monocytes via NF‐kB activation, and its knockdown elicits pro‐inflammatory phenotype in macrophages. These results suggest that upregulation of PARAIL in the short term by PA and LPS can mediate feedback mechanisms to protect from fatty acid‐induced inflammation associated with metabolic disorders, and this protection is lost during downregulation of PARAIL in chronic disease.