DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes

Giordano, A; Luciani, Marco; Gatto, Francesca; Alezz, Monah Abou; Beghè, Chiara; Volpe, Lucrezia della; Migliara, Alessandro; Valsoni, Sara; Genua, Marco; Dzieciątkowska, Monika; Frati, Giacomo; Tahraoui-Bories, Julie; Giliani, Silvia; Orcesi, Simona; Fazzi, Elisa; Ostuni, Renato; D’Alessandro, Angelo; Micco, Raffaella Di; Merelli, Ivan; Lombardo, Angelo; Reijns, Martin A.M.; Gromak, Natalia; Gritti, Angela; Kajaste‐Rudnitski, Anna

doi:10.1084/jem.20211121

Cited by 45 publications

(31 citation statements)

References 131 publications

(190 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mechanisms driving cGAS/STING activation in our AAPV model may be multiple and remain to be further investigated. “Misplaced” cytosolic self-DNA in stressed cells is known to efficiently activate cGAS resulting in IFN-I release ( West et al, 2015 ; Giordano et al, 2022 ), which may contribute to cGAS activation during AAPV progression. On the other hand, extracellular DNA is known to reach the cytosol and activate cGAS/STING in vivo under some conditions ( Gehrke et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

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

Kessler

Viehmann

Krollmann

et al. 2022

Journal of Experimental Medicine

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Kessler

Viehmann

Krollmann

et al. 2022

Journal of Experimental Medicine

View full text Add to dashboard Cite

show abstract

“…It is currently discussed if the SARS-CoV-2 pandemic will lead to a second pandemic of neurodegenerative diseases in the next years but further studies are needed to investigate the direct link of viral induced systemic inflammation and its effects on myelination, synapse organization and neurodegeneration and to correlate the clinically observed neurological symptoms and changes in cognition due to SARS-CoV-2 infection as well as other virus induced or autoimmune/autoinflammatory disorders. Along this line, certain "interferonopathies'' such as Aicardi-Goutières syndrome and SLE are associated with neurological symptoms and cognitive impairment [110][111][112] and studies in mice suggest a detrimental collateral damage of the CNS in the context of a systemic type I Interferon response in certain viral infections [113][114][115][116] . In mice, also chronic presence of IFN-I in the brain alone could negatively affect cognitive function, mediated via modulation of microglial activity 117 .…”

Section: Discussionmentioning

confidence: 99%

The central nervous system’s proteogenomic and spatial imprint upon systemic viral infections with SARS-CoV-2

Radke

Meinhardt

Aschman

et al. 2023

Preprint

View full text Add to dashboard Cite

In COVID-19 neurological alterations are noticed during the systemic viral infection. Various pathophysiological mechanisms on the central nervous system (CNS) have been suggested in the past two years, including the viral neurotropism hypothesis. Nevertheless, neurological complications can also occur independent of neurotropism and at different stages of the disease and may be persistent. Previous autopsy studies of the CNS from patients with severe COVID-19 show infiltration of macrophages and T lymphocytes, especially in the perivascular regions as well as pronounced microglial activation, but without signs of viral encephalitis. However, there is an ongoing debate about long-term changes and cytotoxic effects in the CNS due to the systemic inflammation. Here, we show the brain-specific host response during and after COVID-19. We profile single-nucleus transcriptomes and proteomes of brainstem tissue from deceased COVID-19 patients who underwent rapid autopsy. We detect a disease phase-dependent inflammatory type-I interferon response in acute COVID-19 cases. Integrating single-nucleus RNA sequencing and spatial transcriptomics, we could localize two patterns of reaction to severe systemic inflammation. One neuronal with direct focus on cranial nerve nuclei and one diffusely affecting the whole brainstem, the latter reflecting a bystander effect that spreads throughout the vascular unit and alters the transcriptional state of oligodendrocytes, microglia and astrocytes. Our results indicate that even without persistence of SARS-CoV-2 in the CNS, the tissue activates highly protective mechanisms, which also cause functional disturbances that may explain the neurological symptoms of COVID-19, triggered by strong systemic type-I IFN signatures in the periphery.

show abstract

“…3A) suggesting that STING signaling is not crucial in controlling the growth of Samhd1 Δ/Δ Trp53 -/- -deficient tumors. We and others previously reported that loss of p53 increased DNA damage and potentiated the spontaneous cGAS/STING-dependent IFN response in mice (Hiller et al, 2018) and in iPSCs (Giordano et al, 2022) with a defect in the essential DNA repair enzyme RNaseH2, strongly implicating genome damage in the generation of immune stimulatory DNA in this model. To better understand the lack of an effect of STING-deficiency in our Samhd1 Δ/Δ Trp53 -/- mouse model, we quantified the spontaneous activation of the type I IFN system.…”

Section: Resultsmentioning

confidence: 59%

“…We recently reported evidence that the IFN response in Trex1 -/- mice is linked to DNA replication (Schubert et al, 2022) and similar findings have been reported for SAMHD1 -/- cells (Coquel et al, 2018). In both models, loss of p53 did not amplify the IFN response, while such p53-dependent amplification was observed in cells lacking RNaseH2, in which chromatin fragments activate cGAS (Hiller et al, 2018; Mackenzie et al, 2017; Giordano et al, 2022). This points to a differential involvement of the p53 pathway in the generation of immune stimulatory DNA as a result of DNA replication in cells lacking TREX1 or SAMHD1 compared with post-replicative DNA damage found in RNaseH2-deficient cells.…”

Section: Discussionmentioning

confidence: 91%

cGAS/STING-DEPENDENT SENSING OF ENDOGENOUS RNA

Schumann

Ramon

Schubert

et al. 2022

Preprint

View full text Add to dashboard Cite

Defects in nucleic acid metabolizing enzymes lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing a pathogenic type I interferon response and inflammatory diseases. In these pathophysiological conditions, cGAS-driven IFN production is linked to spontaneous DNA damage. Physiological, or tonic, IFN signaling on the other hand is essential to functionally prime nucleic acid sensing pathways. Here we show that low-level chronic DNA damage in mice lacking the Aicardi-Goutières syndrome gene SAMHD1 reduced tumor-free survival when crossed to a p53-deficient, but not to DNA mismatch repair-deficient background. Increased DNA damage did not result in higher levels of type I interferon. Instead, we found that the chronic interferon response in SAMHD1-deficient mice was driven by the MDA5/MAVS pathway but required functional priming through the cGAS/STING pathway. Our work positions cGAS/STING upstream of tonic IFN signaling and highlights an important role of the pathway in physiological and pathophysiological innate immune priming.SummaryLoss of the dNTPase and DNA repair enzyme SAMHD1 is associated with cancer and causes systemic autoimmunity. We show transformation-promoting spontaneous DNA damage and MDA5-driven but cGAS/STING-dependent chronic type I interferon production in SAMHD1-deficient mice.

show abstract

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes

Cited by 45 publications

References 131 publications

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

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

The central nervous system’s proteogenomic and spatial imprint upon systemic viral infections with SARS-CoV-2

cGAS/STING-DEPENDENT SENSING OF ENDOGENOUS RNA

Contact Info

Product

Resources

About