The Third Man: DNA sensing as espionage in pulmonary vascular health and disease

Abstract

For as long as nucleic acids have been utilized to vertically and horizontally transfer genetic ma-terial, living organisms have had to develop methods of recognizing cytosolic DNA as either pathogenic (microbial invasion) or physiologic (mitosis and cellular proliferation). Derangement in key signaling molecules involved in these pathways of nucleotide sensing result in a family of diseases labeled interferonopathies. An interferonopathy, characterized by constitutive expres-sion of type I interferons, ultimately manifests as severe autoimmune disease at a young age. Afflicted patients present with a constellation of immune-mediated conditions, including primary lung manifestations such as pulmonary fibrosis and pulmonary hypertension. The latter condi-tion is especially interesting in light of the known role that DNA damage plays in a variety of types of inherited and induced pulmonary hypertension, with free DNA detection elevated in the circula-tion of affected individuals. While little is known regarding the role of cytosolic DNA sensing in development of pulmonary vascular disease, exciting new research in the related fields of immu-nology and oncology potentially sheds light on future areas of fruitful exploration. As such, the goal of this review is to summarize the state of the field of nucleic acid sensing, extrapolating common shared pathways that parallel our knowledge of pulmonary hypertension, in a molecular and cell-specific manner. Principles of DNA sensing related to known pulmonary injury inducing stimuli are also evaluated, in addition to potential therapeutic targets. Finally, future directions in pulmonary hypertension research and treatments will be briefly discussed.

Cell dichotomous role of STING in pulmonary hypertension

“…Notably, a recent study of STING pathway analysis in COVID-19 revealed a pathogenic role for STING, contributing to lung inflammation and disease progression 16 . Likewise, STING promotes inflammation in a variety of disparate disease models [17][18][19] , playing an important role in immune homeostasis 20 , contributing in particular to parenchymal lung disease and systemic vasculitis 21 . To date, there are no data on STING involvement in pulmonary vascular disease, although the role of type I IFN in PH have been addressed by different research groups, albeit with contradicting results 22,23 .…”

Non–Interferon-Dependent Role of STING Signaling in Pulmonary Hypertension

“…16 Likewise, STING promotes inflammation in a variety of disparate disease models, [17][18][19][20] playing an important role in anticipatory immune homeostasis, 21 contributing in particular to parenchymal lung disease and systemic vasculitis. 22 Similarly, STING activation in smooth muscle cells was recently reported to result in cell death, contributing to aortic aneurysm, 23 while STING agonist has been shown to promote apoptosis of tumor endothelial cells in different cancer models. 24 Both studies highlight the relevance of STING in the regulation of cells in the vasculature.…”