NF-κB activation enhances STING signaling by altering microtubule-mediated STING trafficking

Zhang, Lulu; Wei, Xubiao; Wang, Zhimeng; Liu, Peiyuan; Hou, Yanfei; Xu, Yifang; Su, Huili; Koci, Matthew D.; Yin, Hong; Zhang, Conggang

doi:10.1016/j.celrep.2023.112185

Cited by 74 publications

(41 citation statements)

References 77 publications

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“…While we cannot exclude that concomitant genetic loss of Atg5 and Sting in muTECs have additional cell-non autonomous effects, which need to be further addressed, our in vitro and in vivo data, indicate that STING is not required for the activation of NF-kB and is dispensable for the major inflammatory effects of autophagy inhibition in TECs, since in the absence of STING, NF-B pathways remain active. Interestingly, while STING is known to mediate the activation of NF-B by recruiting TBK1 34 , recent data posited that NF-B activation, by inhibiting microtubule-mediated STING transport to the lysosome, promotes STING signaling in response to a variety of signals 72 .…”

Section: Discussionmentioning

confidence: 99%

Tumor Endothelial Cell Autophagy Is a Key Vascular-Immune Checkpoint in Melanoma

Verhoeven

Jacobs

Rizzollo

et al. 2023

Preprint

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Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune-excluded tumor phenotype. However, the molecular mechanisms that sustain TEC-mediated immunosuppression remain largely elusive. Here, we show that autophagy ablation in TECs boosts antitumor immunity by supporting infiltration and effector function of T cells, thereby restricting melanoma growth. In melanoma-bearing mice, loss of TEC autophagy leads to the transcriptional expression of an immunostimulatory/inflammatory TEC phenotype driven by heightened NF-kB and STING signaling. In line, single-cell transcriptomic datasets from melanoma patients disclose an enriched InflammatoryHigh/AutophagyLow TEC phenotype in correlation with clinical responses to immunotherapy. Congruently, patients responding to immunotherapy exhibit an increased presence of inflamed vessels, interfacing with infiltrating CD8+ T cells. Mechanistically, STING-dependent immunity in TECs is not critical for the immunomodulatory effects of autophagy ablation, since NF-kB-driven inflammation remains functional in STING/ATG5 double knockout TECs. Hence, autophagy is a principal tumor vascular anti-inflammatory mechanism dampening melanoma antitumor immunity.

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Section: Discussionmentioning

confidence: 99%

Tumor Endothelial Cell Autophagy Is a Key Vascular-Immune Checkpoint in Melanoma

Verhoeven

Jacobs

Rizzollo

et al. 2023

Preprint

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“…However, the adjuvant activity of CFA stems from its ability to stimulate a local innate immune response, leading to a delayed hypersensitivity reaction and an intense inflammatory response at the site of injection 29 . Interestingly, NF-kB signaling in response to cytokines such as IL-6 or IL-1β, enhances STING-mediated immune responses by inhibiting the microtubule-mediated trafficking of STING from the Golgi apparatus to lysosomes for degradation 30 . Additionally, a burst of mitochondrial reactive oxygen species (ROS), during inflammation, can trigger the opening of the mitochondrial permeability transition pore (mPTP), resulting in the extracellular release of mitochondrial DNA (mtDNA).…”

Section: Discussionmentioning

confidence: 99%

Induction of antiviral Interferon-Stimulated Genes (ISGs) by neuronal STING promotes the resolution of pain

Defaye,

Bradaia,

Abdullah

et al. 2023

Preprint

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Nociceptive neurons respond to inflammation, initiating protective reflexes and alerting the host. Here we found that TRPV1 nociceptors express and activate the cytosolic DNA-sensing protein Stimulator of Interferon Genes (STING) in response to inflammation. Neuronal activation of STING promotes signaling through TBK1 and triggers a Type I interferon (IFN-I) response. The absence of STING led to heightened pain responses to chemical irritants or heat. In contrast, mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia. Importantly, several IFN-regulated genes (IRGs) were specific to nociceptor ion channels responsible for controlling neuronal activity and pain threshold. Therefore, STING promotes a pain-resolving IFN-I signaling pathway in nociceptors, thereby preventing sensitization and persistent pain.

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“…Meanwhile, the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway in macrophages plays a central role in mediating the innate and adaptive immunity, and can be activated to release interferons (IFNs) and initiate strong inflammatory responses (Figure a). , Importantly, STING can trigger and regulate the NF-κB signaling pathway. Meanwhile, the activation of NF-κB blocks STING degradation and thus prolongs and increases STING reaction in return . As a result, the synergy between NF-κB and STING triggers cascade-amplified inflammation responses and robust host immune defense .…”

Section: Introductionmentioning

confidence: 99%

“…Meanwhile, the activation of NF-κB blocks STING degradation and thus prolongs and increases STING reaction in return. 26 As a result, the synergy between NF-κB and STING triggers cascade-amplified inflammation responses and robust host immune defense. 27 Therefore, the simulta- Upon recognition of microbial toxins, Toll-like receptor (TLR) located in alveolar macrophages can activate NF-κB, leading to the production of pro-inflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

Bioengineered Neutrophil Extinguisher Targets Cascade Immune Pathways of Macrophages for Alleviating Cytokine Storm in Pneumonia

Zhou,

Chen,

Gao

et al. 2023

ACS Nano

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Cytokine storm is a common complication of COVID-19 pneumonia and has been proven to contribute to high mortality rates. However, current treatment approaches exhibit limited potential to balance immune response and overproduction of inflammatory cytokines, leading to poor therapeutic outcomes. Herein, a smart bioengineered neutrophil, Extinguisher, composed of live neutrophils encapsulating the liposome formulation of NF-κB suppressor MLN4924 and STING inhibitor H-151 (Lip@MH), is developed for alleviating the hyperinflammatory cytokine storm. Extinguisher inherits motility and chemotaxis characteristics of neutrophils, allowing for the specific delivery and sustained release of Lip@MH within inflamed tissues. Subsequently, Lip@ MH effectively transports anti-inflammatory agents into macrophages and synergistically inhibits inflammatory pathways of NF-κB and STING, leading to decreased production of cytokines. In vivo studies demonstrate that Extinguisher not only selectively accumulates at the site of pneumonia caused by Pseudomonas aeruginosa-induced acute lung injury but inhibits the production of inflammatory factors through regulating NF-κB/STING signaling pathways, thereby effectively calming cytokine storm. Importantly, Extinguisher significantly improves therapeutic benefits and survival in mice with acute pneumonia. Therefore, Extinguisher represents an appropriate combination of cell therapy and immunoregulation for cytokine storm intervention and may bring insights into the treatment of COVID-19 pneumonia.

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NF-κB activation enhances STING signaling by altering microtubule-mediated STING trafficking

Cited by 74 publications

References 77 publications

Tumor Endothelial Cell Autophagy Is a Key Vascular-Immune Checkpoint in Melanoma

Tumor Endothelial Cell Autophagy Is a Key Vascular-Immune Checkpoint in Melanoma

Induction of antiviral Interferon-Stimulated Genes (ISGs) by neuronal STING promotes the resolution of pain

Bioengineered Neutrophil Extinguisher Targets Cascade Immune Pathways of Macrophages for Alleviating Cytokine Storm in Pneumonia

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