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

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Long noncoding RNAs (lncRNAs) regulate gene expression in biological processes.
• While lncRNAs are found in immune cells, their functions, particularly in sepsis, are largely unknown.
• Gastric adenocarcinoma predictive long intergenic noncoding RNA (GAPLINC) was previously linked to cancer.

Purpose of the Study:

• To investigate the role of GAPLINC in innate immunity, macrophages, and lipopolysaccharide (LPS)-induced endotoxic shock.
• To explore the mechanism by which GAPLINC influences inflammatory responses.
• To determine GAPLINC's function in sepsis models.

Main Methods:

• Transcriptome analysis of human and mouse macrophages.
• Macrophage differentiation and inflammatory activation studies.
• GAPLINC depletion and overexpression experiments.
• Gaplinc knockout mouse model for LPS-induced endotoxic shock.

Main Results:

• GAPLINC is conserved and highly expressed in differentiated macrophages, down-regulated upon inflammation.
• GAPLINC depletion enhances baseline inflammatory gene expression; overexpression suppresses it.
• Gaplinc knockout mice show enhanced basal inflammation and resistance to LPS shock.
• Increased nuclear NF-κB in knockout mice drives basal immune gene expression, reducing clotting and preventing organ failure.

Conclusions:

• GAPLINC functions as a negative regulator of inflammation.
• GAPLINC plays a critical role in modulating endotoxic shock.
• This study reveals a novel immune function for the lncRNA GAPLINC.