LincRNA-Cox2 functions to regulate inflammation in alveolar macrophages during acute lung injury

Abstract

The respiratory system exists at the interface between our body and the surrounding non-sterile environment; therefore, it is critical for a state of homeostasis to be maintained through a balance of pro- and anti- inflammatory cues. An appropriate inflammatory response is vital for combating pathogens, while an excessive or uncontrolled inflammatory response can lead to the development of chronic diseases. Recent studies show that actively transcribed noncoding regions of the genome are emerging as key regulators of biological processes, including inflammation. LincRNA-Cox2 is one such example of an inflammatory inducible long noncoding RNA functioning to control immune response genes. Here using bulk and single cell RNA-seq, in addition to florescence activated cell sorting, we show that lincRNA-Cox2 is most highly expressed in the lung, particularly in alveolar macrophages where it functions to control immune gene expression following acute lung injury. Utilizing a newly generated lincRNA-Cox2 transgenic overexpressing mouse, we show that it can function in trans to control genes including Ccl3, 4 and 5. This work greatly expands our understanding of the role for lincRNA-Cox2 in host defense and sets in place a new layer of regulation in RNA-immune-regulation of genes within the lung.

What sequencing technologies can teach us about innate immunity*

“…Since this study, we and others have shown that lincRNA-Cox2 is a highly inflammatory inducible gene that functions broadly to regulate immune genes during the innate immune response. [58][59][60][61][62][63][64] Interestingly, using multiple genetic mice models, we found that lincRNA-Cox2 can function both in cis where it regulates the critical immune gene Ptgs2 (Cox2) through an enhancer RNA mechanism as well as in trans to regulate a wide variety of immune genes in macrophages. 62,63 We found that LincRNA-Cox2 can function in trans to negatively regulate basal expression of interferon-stimulated genes through interactions with hnRNPA2/B1 and hnRNPA/B (Figure 3B).…”

“…[58][59][60][61][62][63][64] Interestingly, using multiple genetic mice models, we found that lincRNA-Cox2 can function both in cis where it regulates the critical immune gene Ptgs2 (Cox2) through an enhancer RNA mechanism as well as in trans to regulate a wide variety of immune genes in macrophages. 62,63 We found that LincRNA-Cox2 can function in trans to negatively regulate basal expression of interferon-stimulated genes through interactions with hnRNPA2/B1 and hnRNPA/B (Figure 3B). 58 Interestingly, many lncRNAs that function within the immune system appear to do so through interactions with various hnRNP proteins.…”

Short open reading frame genes in innate immunity: from discovery to characterization

“…Their abundance in the genome is similar to that of protein-coding genes, and many have been shown to contribute to various phenotypes through interactions with proteins, RNA, DNA, or combinations thereof [6,7]. Although only a few per cent of catalogued lncRNAs have been characterized, those that have are implicated in key biological processes including immunity [8,9], cancer [10], viability, and differentiation [6,7]. LncRNAs are often processed similarly to mRNAsspliced, capped, and adenylatedand those that are exported to the cytoplasm are frequently found bound to ribosomes.…”