Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing

Abstract

Autoimmune vasculitis is a group of life-threatening diseases, whose underlying pathogenic mechanisms are incompletely understood, hampering development of targeted therapies. Here, we demonstrate that patients suffering from anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) showed increased activity of the DNA sensor cGAS and enhanced IFN-I signature. To identify potential therapeutic targets, we developed a mouse model for pulmonary AAV that mimics severe disease in patients. Immunogenic DNA accumulated during disease onset, triggering cGAS/STING/IRF3-dependent IFN-I release that promoted endothelial damage, pulmonary hemorrhages, and lung dysfunction. Macrophage subsets played dichotomic roles in disease. While recruited monocyte-derived macrophages were major disease drivers by producing most IFN-β, resident alveolar macrophages contributed to tissue homeostasis by clearing red blood cells and limiting infiltration of IFN-β-producing macrophages. Moreover, pharmacological inhibition of STING, IFNAR-I or its downstream JAK/STAT signaling reduced disease severity and accelerated recovery. Our study unveils the importance of STING/IFN-I axis in promoting pulmonary AAV progression and identifies cellular and molecular targets to ameliorate disease outcome.

Single-cell RNA-sequencing of PBMCs from SAVI patients reveals disease-associated monocytes with elevated integrated stress response

“…Indeed, monocytic infiltrate has been observed, and it is conceivable that they could be composed of the disease-associated monocytes identified in the blood. The role of monocytes and monocytederived macrophages is increasingly recognized in pulmonary fibrosis [50][51][52][53] . Additionally, the integrated stress response, a strongly induced pathway in these monocytes, has also been proposed as an important driver of pulmonary fibrosis 54 , which further supports the hypothesis that the disease-associated monocytes may drive the pulmonary damage in SAVI patients.…”

Opposing roles of resident and infiltrating immune cells in the defence againstLegionella longbeachaevia IL-18R/IFN-γ/ROS axis

“…Vibratome sections of lungs 2 days after infection were analysed as previously described [9]. Briefly, mice were humanely killed by xylazine/ ketamine overdose and lungs inflated with 1 ml of 2% low melting temperature agarose (Promega, US) at 37 °C.…”

“…However, another study found that inducing macrophage apoptosis resulted in an decreased burden of L. pneumophila and L. longbeachae in the lungs of mice [7]. In addition, monocytes that infiltrate the lung after infection and their progeny such as AM-like cells, inflammatory macrophages, and dendritic cells [8][9][10][11], have been shown to be important mediators of defence against L. pneumophila and L. longbeachae [12]. Whereas it is known that monocyte-derived cells (MC) protect against L. pneumophila via production of pro-inflammatory interleukin (IL)-12 [10,12], the mechanisms of protection against L. longbeachae are not clear.…”

GAS-STING: a classical DNA recognition pathways to tumor therapy

“…As part of the innate immune system, the cGAS-STING pathway forms a critical surveillance system that responds to widespread tissue damage and pathogen invasions. Its dysregulation is linked with the pathogenesis of a broad range of human diseases, including infectious diseases, autoimmune diseases, cancer, and neurodegenerative diseases (7)(8)(9)(10)(11).…”