A conserved long noncoding RNA, GAPLINC, modulates the immune response during endotoxic shock
| Autor: | Susan Carpenter, Daisy Kuang, Justin Iwuagwu, Kasthuribai Viswanathan, Ran Song, Sergio Covarrubias, Sol Katzman, Aaron Shulkin, Edward K. Wakeland, Christopher Vollmers, Apple Cortez Vollmers |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Lipopolysaccharides
Male THP-1 Cells Inbred C57BL Transcriptome sepsis Mice 0302 clinical medicine Immunology and Inflammation Gene expression Innate 2.1 Biological and endogenous factors Aetiology innate immunity Cells Cultured Cancer 0303 health sciences Multidisciplinary Cultured NF-kappa B Shock Hematology Biological Sciences Non-coding RNA Shock Septic Long non-coding RNA Cell biology Infectious Diseases 030220 oncology & carcinogenesis Knockout mouse RNA Long Noncoding Female Long Noncoding medicine.symptom Infection Biotechnology Cells 1.1 Normal biological development and functioning Inflammation Biology 03 medical and health sciences Immune system Underpinning research medicine Genetics Animals Humans long noncoding RNA GAPLINC 030304 developmental biology Innate immune system Septic Inflammatory and immune system Immunity Immunity Innate Mice Inbred C57BL inflammation RNA |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 118, iss 7 Proceedings of the National Academy of Sciences of the United States of America |
| Popis: | Significance Inflammation has largely been studied in the context of protein-coding genes. Recent studies have uncovered lncRNAs as important regulators of immunity. The functional characterization of these genes remains an active area of research. In this study, we identify GAPLINC as a functionally conserved lncRNA between human and mouse. GAPLINC depletion results in enhanced expression of immune response genes that are direct NF-κB targets. Astoundingly, we observe that Gaplinc knockout mice show resistance to LPS-induced endotoxic shock and find that basal expression of inflammatory genes prevents clot formation to protect against multiorgan failure and death. These findings have implications in the treatment of sepsis, in which new therapies targeting lncRNAs can contribute valuable information in understanding inflammation and improving patient outcome. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|