LncRNA regulates lung inflammation

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ABSTRACT Lung infections place a major burden on public health worldwide and are the leading cause of death in the United States. Infections caused by gram-negative (G-) bacteria have features that are of particular concern, such as being highly efficient at acquiring antibiotic resistance. Alveolar macrophages (AMs) form the first line of defense in lungs toward microbial pathogens via protective inflammatory responses. The high mortality and morbidity after bacterial infection often result from an imbalance in host defense between bactericidal and an excessive inflammatory response that leads to tissue damage. Despite years of research, the initiation, propagation and regulation of inflammatory lung responses in the presence of G- bacterial infection remains incompletely explored. Only recently has it been recognized that long non-coding RNAs (lncRNA) are extensively expressed in various immune cells including the macrophages, but very little has been known about their functional roles. We screened lncRNA expressions in mouse lungs after intra-tracheal instillation of LPS, Klebsiella pneumoniae (K.pneumoniae) and Escherichia coli (E.coli). LncRNA lincenc1 exhibited the greatest induction in expression among treated groups. Functionally, lincenc1 promotes the classical activation (M1) of macrophages and the secretion of pro-inflammatory cytokines. Deletion of lincenc1 in AMs using the specific antisense oligonucleotides (ASO) in vivo significantly reduces the LPS-induced leukocyte infiltration and alveolar edema, when compared with the control group. Furthermore, inhibition of lincenc1 using ASO down-regulates multiple inflammatory cytokines and chemokines (Il-1β, Il-6, Cxcl1 and Cxcl2), detected in BALF after exposure to LPS. Mechanistically, we found that lincenc1 co-localizes with NLRP3 components in the presence of LPS, suggesting a regulatory role of lincenc1 on NLRP3 inflammasone activation. Based on our published and preliminary data, our central hypothesis is that lncRNA lincenc1 facilitates G-bacteria/LPS induced lung inflammation via promoting classical activation of macrophages through NLRP3 inflammasome assembly and activation. We propose three specific aims: Specific Aim I: To determine the role of lncRNA lincenc1 in macrophage activation in vitro. Specific Aim II: To determine the role of lincenc1 in lung inflammation in vivo. Specific Aim III: To determine whether lincenc1 serves as a potential therapeutic target in vivo.