TY - JOUR
T1 - A conserved long noncoding RNA, GAPLINC, modulates the immune response during endotoxic shock
AU - Vollmers, Apple Cortez
AU - Covarrubias, Sergio
AU - Kuang, Daisy
AU - Shulkin, Aaron
AU - Iwuagwu, Justin
AU - Katzman, Sol
AU - Song, Ran
AU - Viswanathan, Kasthuribai
AU - Vollmers, Christopher
AU - Wakeland, Edward
AU - Carpenter, Susan
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank A.J. Crawford for help with generating Circos plots to visualize RNA-Seq data and all members of the Carpenter Laboratory. We thank Dr. Judith Hellman for her helpful insights into mechanisms occurring during sepsis. This work was supported by the NIH (R21AR070973, R01AI148413, to S. Carpenter). A.C.V. was supported by the NIH Predoctoral Training Grant (T32 GM008646), the Ford Predoctoral Fellowship, and the Howard Hughes Medical Institute Gilliam Fellowship.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/2/16
Y1 - 2021/2/16
N2 - 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.
AB - 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.
KW - Long noncoding RNA | inflammation | GAPLINC | innate immunity | sepsis
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U2 - 10.1073/pnas.2016648118
DO - 10.1073/pnas.2016648118
M3 - Article
C2 - 33568531
AN - SCOPUS:85101041553
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 7
M1 - e2016648118
ER -