Thematic Minireview Series: Inflammatory transcription confronts homeostatic disruptions

Abstract

In this Thematic Minireview Series, three stimulating articles are presented: one on long non-coding RNAs, another on the ligand-activated transcription factor aryl hydrocarbon receptor, and the third on how docosanoids modulate transcriptionally modulated homeostasis and ultimately cell survival in the retina and brain.Relationships are key, both in life and in the life of a cell. This is particularly important when cells need to confront potential disruptors of homeostasis to prevent chaos and disease onset. The homeostasis concept was developed by Harvard physiologist Walter Bradford Cannon in 1932 (1). Today we bring homeostasis to the molecular level when considering how the inflammatory response triggers transcriptional regulation to sustain cellular integrity. The response is initially a defensive reaction that includes immune cells, blood vessels, neurons, astrocytes, macrophages, microglia, retinal pigment epithelial cells, and other cells to sustain homeostasis by removing the triggering factor(s) and cell debris and then to set in motion cellular and tissue restoration. Some of the responses overcome the homeostasis disruptor, leading to resolution, whereas others would be unable to restore balance, setting up the onset and progression of diseases often reflected in disrupted homeostasis and the triggering of a complex, failed inflammatory response. In many tumors, inflammation orchestrates a microenvironment beneficial to proliferation, cancer cell survival, and migration. The principles governing these crucial responses are beginning to be unraveled at the transcription level. Furthermore, there is an intimate relationship between the immune system and the inflammatory response at the transcriptional level that is allowing for integrated responses and deciphering of the molecular principles engaged. In fact, to make this happen, there must be a convergence of genetic and environmental factors (pollutants), as well as diet and the microbiome. lncRNAs and their transcriptional control of inflammatory responsesMathy and Chen (2) refer to the evolving role of long noncoding RNAs (lncRNAs) 2 as transcriptional regulators of the inflammatory response. A group of lncRNAs is induced as part of the response to inflammation and acts as an enhancer or a suppressor of inflammatory transcription, with members behaving as scaffolds with RNA-binding proteins in chromatinremodeling complexes. lncRNAs augment the inflammatory response by enhancing the transcription of pro-inflammatory target genes or inflammatory signals. On the other hand, lncRNAs suppress or limit the magnitude of the inflammatory response by limiting the transcription of pro-inflammatory cytokines, or of the availability of inflammatory signal pathways. The review also discusses specific examples such as lincRNA-EPS, which down-regulates expression of immune response genes in macrophages. Upon microbial activation, this suppression is released, and gene transcription is activated. Also lincRNA-Cox-2 performs both as an enhancer and as a suppresso...