Obesity and diabetes are associated with chronic inflammation induced by the elevated circulating levels of Palmitic acid (PA) and also result from impaired resolution of inflammation in macrophages. Here, we examined the role of PA-induced long non-coding RNAs (lncRNAs) in the resolution of inflammation. Our RNA-seq analysis showed that PA induced several lncRNAs including a novel PA-regulatedanti-nflammatoryIncRNA (PARAIL) in CD14+ human monocytes. We found PARAIL was also upregulated by lipopolysaccharide and bacterial infection in human monocytes and macrophages, suggesting its role in adaptive immunity. PARAIL knockdown in human macrophages enhanced PA-induced key inflammatory cytokine genes and delayed resolution of inflammation. RNA-pulldown coupled with mass spectrometry showed that PARAIL interacts with Hu Antigen R (HuR) an RNA-binding and AU-rich element (ARE) binding protein that regulates inflammation. We also identified AREs in PARAIL that interact with HuR. Further, knockdown of HuR and PARAIL additively increased the expression of inflammatory genes compared to knockdown of HuR or PARAIL alone suggesting PARAIL mediated resolution of inflammation relies on HuR function. Moreover, PARAIL knockdown decreased HuR protein levels, suggesting PARAIL increases HuR stability to decrease inflammatory genes and promote resolution of inflammation. In addition, Parail was also downregulated in macrophages from mouse models of diabetes and accelerated atherosclerosis. Together, these data suggest that upregulation of PARAIL under inflammatory conditions can contribute to unique feedback pro-resolution mechanisms via PARAIL-HuR interaction to restrain fatty acid-induced inflammation. However, PARAIL downregulation during obesity/ diabetes can further augment inflammation. LncRNAs like PARAIL therefore represent novel tools to combat inflammation associated with these metabolic disorders.
V.S.Tanwar: None. R.Natarajan: None. M.A.Reddy: None. S.Das: None. V.Samara: None. M.Abdollahi: None. S.Dey: None. R.Ganguly: None. L.L.Lanting: None. K.Stapleton: None.
National Institutes of Health (NIH RDK 065073)