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

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.

Long noncoding RNAs in bacterial infection

“…The limited primary sequence conservation of lncRNAs between humans and rodents (Roux et al, 2017) could be a major obstacle in this context. Among the few immune-regulatory lncRNAs found to be conserved between humans and mice, so far, are CARLR, IL7-AS and GAPLINC, which regulate pro-inflammatory cytokine production (Castellanos-Rubio et al, 2017;Roux et al, 2017;Vollmers et al, 2021). An important task for the future will be to identify further locus-or structure conserved orthologues and functional equivalents of human immune-regulatory lncRNAs in mice.…”

“…GAPLINC deficiency enhanced baseline expression of NFκB dependent genes in human cells and mice. This pre-activation of immune-response genes protected GAPLINC-deficient mice from LPS-induced endotoxin shock-a fulminant inflammatory response syndrome, associated with high mortality (Vollmers et al, 2021). Other examples of lncRNAs suppressing premature immune responses, which are downregulated upon bacterial PAMP-stimulation, are lincRNA-EPS (Atianand et al, 2016) and lnc13 in murine phagocytes.…”

“…Besides pro-inflammatory, PRR-inducible lncRNAs, several immunosuppressive lncRNAs were found to be downregulated upon bacterial PAMP-stimulation, thereby contributing to the progression of the immune response. GAPLINC, for instance, is a functionally and positionally conserved lncRNA which is downregulated upon human and murine macrophage stimulation with various PRR ligands, including bacterial LPS (Vollmers et al, 2021). GAPLINC deficiency enhanced baseline expression of NFκB dependent genes in human cells and mice.…”

LncRNA GAPLINC Promotes Renal Cell Cancer Tumorigenesis by Targeting the miR-135b-5p/CSF1 Axis

“…Subsequently, GAPLINC was found to be highly expressed in hepatocellular carcinoma (44) and non-small-cell lung cancer (45) and was found to promote cancer through different mechanisms. Vollmers et al found that GAPLINC knockout mice showed resistance to endotoxic shock induced by lipopolysaccharide (46). At the same time, Mo and other studies have shown that GAPLINC can promote the tumor-like biological behavior offibroblast-like synoviocytes in patients with rheumatoid arthritis through a ceRNA mechanism (47).…”

Circulating Long Non-Coding RNAs as Novel Potential Biomarkers for Osteogenic Sarcoma

“…Several lines of evidence have shown that lncRNAs are capable of influencing different cellular functions that are critical to tumorigenesis, such as cell proliferation, differentiation, migration, immune response, and apoptosis [41][42][43][44][45][46][47]. Furthermore, lncRNAs have been found to act as tumor suppressors or oncogenes [48][49][50][51], and, of note, a number of lncRNAs have been reported to be significantly deregulated in tumors [52][53][54][55].…”