A conserved long noncoding RNA, GAPLINC, modulates the immune response during endotoxic shock
Open Access
- 10 February 2021
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 118 (7)
- https://doi.org/10.1073/pnas.2016648118
Abstract
Recent studies have identified thousands of long noncoding RNAs (lncRNAs) in mammalian genomes that regulate gene expression in different biological processes. Although lncRNAs have been identified in a variety of immune cells and implicated in immune response, the biological function and mechanism of the majority remain unexplored, especially in sepsis. Here, we identify a role for a lncRNA—gastric adenocarcinoma predictive long intergenic noncoding RNA (GAPLINC)—previously characterized for its role in cancer, now in the context of innate immunity, macrophages, and LPS-induced endotoxic shock. Transcriptome analysis of macrophages from humans and mice reveals that GAPLINC is a conserved lncRNA that is highly expressed following macrophage differentiation. Upon inflammatory activation, GAPLINC is rapidly down-regulated. Macrophages depleted of GAPLINC display enhanced expression of inflammatory genes at baseline, while overexpression of GAPLINC suppresses this response. Consistent with GAPLINC-depleted cells, Gaplinc knockout mice display enhanced basal levels of inflammatory genes and show resistance to LPS-induced endotoxic shock. Mechanistically, survival is linked to increased levels of nuclear NF-κB in Gaplinc knockout mice that drives basal expression of target genes typically only activated following inflammatory stimulation. We show that this activation of immune response genes prior to LPS challenge leads to decreased blood clot formation, which protects Gaplinc knockout mice from multiorgan failure and death. Together, our results identify a previously unknown function for GAPLINC as a negative regulator of inflammation and uncover a key role for this lncRNA in modulating endotoxic shock.Funding Information
- HHS | NIH | National Institute of Allergy and Infectious Diseases (R01AI148413)
- HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR070973)
- HHS | NIH | National Institute of General Medical Sciences (T32 GM008646)
This publication has 27 references indexed in Scilit:
- The long noncoding RNA THRIL regulates TNFα expression through its interaction with hnRNPLProceedings of the National Academy of Sciences of the United States of America, 2013
- A Long Noncoding RNA Mediates Both Activation and Repression of Immune Response GenesScience, 2013
- Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeatNature, 2012
- Isolation of Mouse Peritoneal Cavity CellsJournal of Visualized Experiments, 2010
- Transcriptional control of the inflammatory responseNature Reviews Immunology, 2009
- Harmful molecular mechanisms in sepsisNature Reviews Immunology, 2008
- Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretaseNature Medicine, 2008
- Uncovering a Macrophage Transcriptional Program by Integrating Evidence from Motif Scanning and Expression DynamicsPLoS Computational Biology, 2008
- FUNDAMENTALS OF PLANARIAN REGENERATIONAnnual Review of Cell and Developmental Biology, 2004
- Phosphorylation Meets Ubiquitination: The Control of NF-κB ActivityAnnual Review of Immunology, 2000