Plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis

Li, Yubin; Bax, Christina E.; Patel, Jay; Vazquez, Thomas; Ravishankar, Adarsh; Bashir, Muhammad M.; Grinnell, Madison; Diaz, DeAnna; Werth, Victoria P.

doi:10.7150/thno.59152

Cited by 21 publications

(27 citation statements)

References 57 publications

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“…A large amount of data has accumulated to suggest that EVs can activate several inflammatory pathways. For example, circulating EVs isolated from patients with dermatomyositis triggered pro-inflammatory cytokine production, including type I interferon production, through activation of the STING pathway by EV-associated double-stranded DNA 96 . However, it is yet to be clarified to what extent EVs participate in triggering or maintaining progression in different autoimmune diseases.…”

Section: Autoimmunity and Transplantationmentioning

confidence: 99%

The roles of extracellular vesicles in the immune system

2022

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The twenty-first century has witnessed major developments in the field of extracellular vesicle (EV) research, including significant steps towards defining standard criteria for the separation and detection of EVs. The recent recognition that EVs have the potential to function as biomarkers or as therapeutic tools has attracted even greater attention to their study. With this progress in mind, an updated comprehensive overview of the roles of EVs in the immune system is timely. This Review summarizes the roles of EVs in basic processes of innate and adaptive immunity, including inflammation, antigen presentation, and the development and activation of B cells and T cells. It also highlights key progress related to deciphering the roles of EVs in antimicrobial defence and in allergic, autoimmune and antitumour immune responses. It ends with a focus on the relevance of EVs to immunotherapy and vaccination, drawing attention to ongoing or recently completed clinical trials that aim to harness the therapeutic potential of EVs.

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Section: Autoimmunity and Transplantationmentioning

confidence: 99%

The roles of extracellular vesicles in the immune system

2022

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“…In addition, DM plasma-derived EVs have been found to trigger proinflammatory cytokine (IFNβ, TNFα and IL-6) release and STING signalling pathway activation in circulating immune cells. The activated STING pathway is preferentially mediated by EV-dsDNA (Li et al, 2021). DE proteins have also been found in DM serum EVs.…”

Section: Discussionmentioning

confidence: 98%

The Functional Roles of RNAs Cargoes Released by Neutrophil-Derived Exosomes in Dermatomyositis

Zuo

Liu

et al. 2021

Front. Pharmacol.

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Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by cutaneous manifestations. We first identified the profiles of noncoding RNAs (lncRNAs and miRNAs) in peripheral neutrophil exosomes (EXOs) of DM patients and explored their potential functional roles. Bioinformatics analyses were performed with R packages. Real-time quantitative PCR was used to validate the altered RNAs in DM neutrophil EXO-stimulated human dermal microvascular endothelial cells (HDMECs) and human skeletal muscle myoblasts (HSkMCs). In DM neutrophil EXOs, 124 upregulated lncRNAs (with 1,392 target genes), 255 downregulated lncRNAs (with 1867 target genes), 17 upregulated miRNAs (with 2,908 target genes), and 15 downregulated miRNAs (with 2,176 target genes) were identified. GO analysis showed that the differentially expressed (DE) lncRNAs and DE miRNAs participated in interleukin-6 and interferon-beta production, skeletal muscle cell proliferation and development, and endothelial cell development and differentiation. KEGG analysis suggested that DE lncRNAs and DE miRNAs were enriched in the PI3K–Akt, MAPK, AMPK and FoxO signalling pathways. Many novel and valuable DE lncRNAs and DE miRNAs interacted and cotargeted in the PI3K–Akt, MAPK, AMPK and FoxO signalling pathways. Our study suggests that neutrophil EXOs participate in DM pathogenesis through lncRNAs and miRNAs in the PI3K–Akt, MAPK, AMPK and FoxO signalling pathways.

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“…Some of these patients have been reported to be improved by JAK inhibitors [87,88]. Of interest, STING activation by DNA containing extracellular vesicles seemed to drive inflammation in dermatomyositis [89]. These data suggest that STING pathway might be central to the pathophysiology of the pulmonary involvement in these more common diseases and that deciphering the lung pathology in SAVI could be relevant to them.…”

Section: Dermatomyositis and Systemic Lupus Erythematosus (Sle)mentioning

confidence: 90%

Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

David

Frémond

2022

Cells

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STING-associated vasculopathy with onset in infancy (SAVI) is a type I interferonopathy caused by gain-of-function mutations in STING1 encoding stimulator of interferon genes (STING) protein. SAVI is characterized by severe inflammatory lung disease, a feature not observed in previously described type I interferonopathies i.e., Mendelian autoinflammatory disorders defined by constitutive activation of the type I interferon (IFN) pathway. Molecular defects in nucleic acid metabolism or sensing are central to the pathophysiology of these diseases, with such defects occurring at any step of the tightly regulated pathway of type I IFN production and signaling (e.g., exonuclease loss of function, RNA-DNA hybrid accumulation, constitutive activation of adaptor proteins such as STING). Among over 30 genotypes, SAVI and COPA syndrome, whose pathophysiology was recently linked to a constitutive activation of STING signaling, are the only type I interferonopathies presenting with predominant lung involvement. Lung disease is the leading cause of morbidity and mortality in these two disorders which do not respond to conventional immunosuppressive therapies and only partially to JAK1/2 inhibitors. In human silicosis, STING-dependent sensing of self-DNA following cell death triggered by silica exposure has been found to drive lung inflammation in mice and human models. These recent findings support a key role for STING and nucleic acid sensing in the homeostasis of intrinsic pulmonary inflammation. However, mechanisms by which monogenic defects in the STING pathway lead to pulmonary damages are not yet fully elucidated, and an improved understanding of such mechanisms is fundamental to improved future patient management. Here, we review the recent insights into the pathophysiology of SAVI and outline our current understanding of self-nucleic acid-mediated lung inflammation in humans.

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Plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis

Cited by 21 publications

References 57 publications

The roles of extracellular vesicles in the immune system

The roles of extracellular vesicles in the immune system

The Functional Roles of RNAs Cargoes Released by Neutrophil-Derived Exosomes in Dermatomyositis

Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

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