The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps

Apel, Falko; Andreeva, Liudmila; Knackstedt, Lorenz Sebastian; Streeck, Robert; Frese, Christian K.; Goosmann, Christian; Hopfner, Karl‐Peter; Zychlinsky, Arturo

doi:10.1126/scisignal.aax7942

Cited by 107 publications

(100 citation statements)

References 92 publications

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“…Furthermore, it was observed that LL-37 could protect NET-derived DNA in SLE, and could help transport extracellular self-DNA into monocytes to stimulate the cGAS/STING pathway 55 , 56 . A recent study also showed that the cytosolic DNA sensor cGAS could recognize NETs and mediate immune cell activation during infection 57 . We believe further studies will be required to help understand the role of circulating EVs mediated type I IFN in DM pathogenesis.…”

Section: Discussionmentioning

confidence: 97%

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

Li¹,

Bax²,

Patel³

et al. 2021

Theranostics

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Objectives: Extracellular vesicles (EVs) are lipid bilayer membrane vesicles that are present in various bodily fluids and have been implicated in autoimmune disease pathogenesis. Type I interferons (IFN), specifically IFN-β, are uniquely elevated in dermatomyositis (DM). The stimulator of interferon genes (STING) works as a critical nucleic acid sensor and adaptor in type I IFN signaling with possible implications in autoimmune diseases such as DM. In the current study, we investigated whether circulating EVs contribute to proinflammatory effects in DM, whether these proinflammatory responses are mediated by the STING signaling pathway, and if so, by what mechanism STING is activated. Methods: We collected and characterized EVs from plasma of healthy controls (HC) and DM patients; analyzed their abilities to trigger proinflammatory cytokines release by ELISA, and explored STING signaling pathway activation using immunoblot and immunofluorescent staining. STING signaling pathway inhibitors and RNAi were used to further investigate whether STING was involved in EVs-triggered proinflammatory response. DNase/lipid destabilizing agent was utilized to digest EVs and their captured DNA contents to evaluate how EVs triggered STING-mediated proinflammatory response in DM. Results: EVs isolated from DM plasma triggered proinflammatory cytokines including type I IFN release with STING signaling pathway activation. The activated STING pathway was preferentially mediated by dsDNA captured by EVs. Suppression of STING or its downstream signaling proteins attenuated the EVs-mediated proinflammatory response. Conclusions: Plasma-derived, DNA containing-EVs induced STING-mediated proinflammatory effects in DM. Targeting the STING pathway may be a potential therapeutic approach for DM.

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Section: Discussionmentioning

confidence: 97%

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

Li¹,

Bax²,

Patel³

et al. 2021

Theranostics

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show abstract

“…Another example of cytosolic chromatin activating cGAS is neutrophil extracellular traps (NETs), which are released by neutrophils during a specific form of regulated cell death called NETosis. These structures, composed of chromatin and antimicrobial molecules, are phagocytosed by macrophages and translocate into the cytoplasm, where they activate cGAS (Apel et al , 2021). As in the case of micronuclei, NETs expose aberrant chromatin structures to an excess of cytosolic cGAS, again possibly exhibiting too few acidic patches to inhibit cGAS.…”

Section: A Cytosolic Dna Sensor In the Nucleusmentioning

confidence: 99%

Nuclear cGAS: guard or prisoner?

Mann

Hopfner

2021

The EMBO Journal

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cGAS, an innate immune sensor of cellular stress, recognizes double‐stranded DNA mislocalized in the cytosol upon infection, mitochondrial stress, DNA damage, or malignancy. Early models suggested that cytosolic localization of cGAS prevents autoreactivity to nuclear and mitochondrial self‐DNA, but this paradigm has shifted in light of recent findings of cGAS as a predominantly nuclear protein tightly bound to chromatin. This has raised the question how nuclear cGAS is kept inactive while being surrounded by chromatin, and what function nuclear localization of cGAS may serve in the first place? Cryo‐EM structures have revealed that cGAS interacts with nucleosomes, the minimal units of chromatin, mainly via histones H2A/H2B, and that these protein–protein interactions block cGAS from DNA binding and thus prevent autoreactivity. Here, we discuss the biological implications of nuclear cGAS and its interaction with chromatin, including various mechanisms for nuclear cGAS inhibition, release of chromatin‐bound cGAS, regulation of different cGAS pools in the cell, and chromatin structure/chromatin protein effects on cGAS activation leading to cGAS‐induced autoimmunity.

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“…In addition, degradation and inhibition of NETs suppressed the activation of STING signaling. Recent studies also highlight that NETs are responsible for STING activation during in ammatory or immune diseases [11,22]. Therefore, STING-mediated in ammatory response may link NETs and PA formation.…”

Section: Discussionmentioning

confidence: 99%

NETs Enhance STING To Promote Surgical Adhesion

Shen

Wang

et al. 2021

Preprint

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Background Postoperative adhesion (PA) following abdominal surgery may cause bowel obstruction, chronic pain, infertility, or even death. Knowledge of adhesion biology is limited, and preventive agents in clinical trials have failed to achieve efficacy. Results In the present study, we showed that neutrophils accumulate in the injured peritoneum at early stage of PA, and neutrophils within the ischemic buttons undergo cell death and form neutrophil extracellular traps (NETs) that contribute to PA. Neutrophil depletion reduces adhesion burden at 7 days after adhesion induction. Peptidylarginine deiminase 4 (PAD4), an essential enzyme for NET formation, is increased in ischemic buttons. Degradation of NETs by DNase 1 and suppression of NET formation by pharmacologic inhibition of PAD4 alleviated adhesion burden, collogen deposition and fibrosis formation. Mechanistically, administration of DNase I and PAD inhibitor reduces STING-mediated inflammatory response. STING deficiency attenuates adhesion burden, collogen deposition, and α-SMA production in the adhesive tissues at 7 days after surgery. Conclusions Collectively, our findings reveal NETs/STING signaling as a therapeutic target to prevent PA.

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The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps

Cited by 107 publications

References 92 publications

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

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

Nuclear cGAS: guard or prisoner?

NETs Enhance STING To Promote Surgical Adhesion

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