A conserved long noncoding RNA, GAPLINC, modulates the immune response during endotoxic shock

Apple Cortez Vollmers, Sergio Covarrubias, Daisy Kuang, Aaron Shulkin, Justin Iwuagwu, Sol Katzman, Ran Song, Kasthuribai Viswanathan, Christopher Vollmers, Edward Wakeland, Susan Carpenter

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article numbere2016648118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number7
DOIs
StatePublished - Feb 16 2021

Keywords

  • Long noncoding RNA | inflammation | GAPLINC | innate immunity | sepsis

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'A conserved long noncoding RNA, GAPLINC, modulates the immune response during endotoxic shock'. Together they form a unique fingerprint.

Cite this