The long noncoding RNA lnc-FAM164A1-ACLY axis promotes pro-inflammatory responses in human primary macrophages: a systems approach

Introduction Macrophages play a key role in inflammatory diseases. We aimed to identify long noncoding RNAs that regulate pro-inflammatory activation of human macrophages. Methods We performed human lncRNA microarray analysis in LPS-stimulated primary human macrophages. We then carried out loss-of-function and gain-of-function experiments, luciferase reporter assays, RNA pulldown, RNA immunoprecipitation, and mouse endotoxemia studies, including humanized mouse models. Results We identified 11 lncRNAs that were significantly increased by LPS. Among them, lnc-FAM164A1 was selected for further study. Silencing of lnc-FAM164A1 by antisense oligonucleotides or siRNA reduced the LPS-induced expression of pro-inflammatory cytokines, including CCL2, IL-6, and TNF-α. In contrast, enforced expression of lnc FAM164A1 enhanced inflammatory responses in human and mouse macrophages. lnc FAM164A1 also promoted NF-κB-related signaling. RNA pulldown and RNA immunoprecipitation identified ACLY as an lnc-FAM164A1 -associated protein. ACLY silencing reduced the inflammatory effects induced by lnc-FAM164A1 . Discussion These findings support that human lnc-FAM164A1 promotes pro-inflammatory activation of macrophages through its interaction with ACLY and NF-κB-related signaling.