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 levels of cGAMP and enhanced IFN-I signature. To identify disease mechanisms and 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 outcomes.

Tissue inflammation induced by constitutively active STING is mediated by enhanced TNF signaling

“…Pharmacological inhibition of STING activation prevented the manifestation of this disease. In the same line it was published that the progression of ANCA-associated vasculitis is dependent on activation of cGAS/STING/IRF3 axis (Kessler et al, 2022). Blockade of STING activation improved the severity of this disease significantly.…”

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.…”

Innate Immune Response to Viral Vectors in Gene Therapy

“…The ITR structure of the AAV genome may activate cytoplasmic DNA receptors. Studies have demonstrated that rAAV can induce cGAS and antiviral genes such as TNF-α and IFN-γ [ 105 ]. The ITR, located at either end of the AAV or within the bidirectional promoter, can generate reverse complementary positive-strand RNA and negative-strand RNA.…”

“…Then, TLRs activate NF-κB and IRF7 via MyD88 signaling pathway, this activation ultimately regulates the production of IFN-I and ISGs [ 13 , 103 , 104 ]. (B) The ITR structure of the AAV genome may activate cytoplasmic DNA to induce cGAS and antiviral genes and activate the cGAS-STING signaling pathway [ 105 ]. (C) Due to the promoter activity of the ITR of AAV, AAV may form dsRNA in target cells and trigger the RIG-I/MDA5-mediated RLR-MAVS innate immune signaling pathway [ 83 , 106 ].…”