STING controls nociception via type I interferon signalling in sensory neurons

Donnelly, Christopher R.; Jiang, Changyu; Andriessen, Amanda S.; Wang, Kaiyuan; Wang, Zilong; Ding, Huiping; Zhao, Junli; Luo, Xin; Lee, Michael S.; Lei, Yu; Maixner, William; Ko, Mei‐Chuan; Ji, Ru-Rong

doi:10.1038/s41586-020-03151-1

Cited by 142 publications

(190 citation statements)

References 48 publications

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“…No apparent sex differences were observed, as the therapeutic effect of DMXAA on bone cancer pain existed in both male and female mice (Supplementary Fig. 1a-d), which is congruent with our previous report 23 . In addition, we observed no differences in body weight between the vehicle-and DMXAA-treated groups (Fig.…”

Section: Resultssupporting

confidence: 92%

“…To formally test the contribution of STING signaling in peripheral sensory neurons, we utilized mice lacking STING selectively in sensory neurons (STING fx/fx ; Na v 1.8-Cre; STING-cKO) or their wildtype littermates. Similar to STING gt/gt mice, STING-cKO mice exhibit mechanical hypersensitivity at baseline relative to STING-WT littermate controls, which we previously reported 23 . Following innoculation with LLC cells via intrafemoral injection, STING-WT and STING-cKO mice were administered vehicle, DMXAA, or ADU-S100 at d3 and d7.…”

Section: Resultssupporting

confidence: 59%

“…Given that cancer-induced bone pain in our model is transduced by peripheral nociceptors in the dorsal root ganglion (DRG), we next sought to determine whether STING signaling in peripheral sensory neurons contributes to the antinociceptive effects of STING agonists in bone cancer pain. Given our previous report in which we demonstrated that STING agonists can directly suppress nociceptor hyperexcitability in a chemotherapy-induced peripheral neuropathy (CIPN) model of chronic pain 23 , we posited that STING agonists may also acutely attenuate bone cancer-induced hyperexcitability of peripheral nociceptors, To test this hypothesis, WT mice were inoculated with LLC cells to establish bone cancer models and lumbar L3-L5 DRGs were isolated on d11 and incubated ex vivo with vehicle or DMXAA (30 µM) for 2 h followed by patch clamp recordings to measure nociceptor excitability (Fig. 4a).…”

Section: Resultsmentioning

confidence: 95%

“…These studies have led to the exploration of ADU-S100 and other small molecule STING agonists to be tested as potential immunotherapy agents in several ongoing clinical trials 21,22 . Our recent study has shown that STING agonists could effectively control nociception in naïve animals and animals with pathological pain 23 . However, it remains unclear if STING agonists are effective in treating bone cancer, especially given that bone marrow is regarded to be an immunosuppressive tumor microenvironment 24 .…”

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confidence: 99%

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STING suppresses bone cancer pain via immune and neuronal modulation

et al. 2021

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Patients with advanced stage cancers frequently suffer from severe pain as a result of bone metastasis and bone destruction, for which there is no efficacious treatment. Here, using multiple mouse models of bone cancer, we report that agonists of the immune regulator STING (stimulator of interferon genes) confer remarkable protection against cancer pain, bone destruction, and local tumor burden. Repeated systemic administration of STING agonists robustly attenuates bone cancer-induced pain and improves locomotor function. Interestingly, STING agonists produce acute pain relief through direct neuronal modulation. Additionally, STING agonists protect against local bone destruction and reduce local tumor burden through modulation of osteoclast and immune cell function in the tumor microenvironment, providing long-term cancer pain relief. Finally, these in vivo effects are dependent on host-intrinsic STING and IFN-I signaling. Overall, STING activation provides unique advantages in controlling bone cancer pain through distinct and synergistic actions on nociceptors, immune cells, and osteoclasts.

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Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 59%

Section: Resultsmentioning

confidence: 95%

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confidence: 99%

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STING suppresses bone cancer pain via immune and neuronal modulation

et al. 2021

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“…Stimulator of interferon genes (STING)-associated vasculopathy(SAVI)caused by mutation of TMEM173 gene is a system disruption of inborn innate immune disorders characterized by neonatal onset of autoinflammation diseases (Ahn and Barber, 2014 ). STING as an adaptor protein could induce antiviral type I IFN signaling thus signals downstream of viral (Siedel et al, 2020 ; Donnelly et al, 2021 ). Nrf2 as an important negative regulator engage on STING repression and destabilization.…”

Section: The Candidate Mechanisms Of Itaconatementioning

confidence: 99%

The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities

et al. 2021

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Metabolites have recently been found to be involved in significant biological regulation and changes. Itaconate, an important intermediate metabolite isolated from the tricarboxylic acid cycle, is derived from cis-aconitate decarboxylation mediated by immune response gene 1 in mitochondrial matrix. Itaconate has emerged as a key autocrine regulatory component involved in the development and progression of inflammation and immunity. It could directly modify cysteine sites on functional substrate proteins which related to inflammasome, signal transduction, transcription, and cell death. Itaconate can be a connector among immunity, metabolism, and inflammation, which is of great significance for further understanding the mechanism of cellular immune metabolism. And it could be the potential choice for the treatment of inflammation and immune-related diseases. This study is a systematic review of the potential mechanisms of metabolite associated with different pathology conditions. We briefly summarize the structural characteristics and classical pathways of itaconate and its derivatives, with special emphasis on its promising role in future clinical application, in order to provide theoretical basis for future research and treatment intervention.

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Neurotrophin Pathway Receptors NGFR and TrkA Control Perineural Invasion, Metastasis, and Pain in Oral Cancer

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Aouizerat

et al. 2022

Advanced Biology

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Oral squamous cell carcinoma (OSCC) patients suffer from poor survival due to metastasis or locoregional recurrence, processes that are both facilitated by perineural invasion (PNI). OSCC has higher rates of PNI than other cancer subtypes, with PNI present in 80% of tumors. Despite the impact of PNI on oral cancer prognosis and pain, little is known about the genes that drive PNI, which in turn drive pain, invasion, and metastasis. In this study, clinical data, preclinical, and in vitro models are leveraged to elucidate the role of neurotrophins in OSCC metastasis, PNI, and pain. The expression data in OSCC patients with metastasis, PNI, or pain demonstrate dysregulation of neurotrophin genes. TrkA and nerve growth factor receptor (NGFR) are focused, two receptors that are activated by NGF, a neurotrophin expressed at high levels in OSCC. It is demonstrated that targeted knockdown of these two receptors inhibits proliferation and invasion in an in vitro and preclinical model of OSCC, and metastasis, PNI, and pain. It is further determined that TrkA knockdown alone inhibits thermal hyperalgesia, whereas NGFR knockdown alone inhibits mechanical allodynia. Collectively the results highlight the ability of OSCC to co-opt different components of the neurotrophin pathway in metastasis, PNI, and pain.

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STING controls nociception via type I interferon signalling in sensory neurons

Cited by 142 publications

References 48 publications

STING suppresses bone cancer pain via immune and neuronal modulation

STING suppresses bone cancer pain via immune and neuronal modulation

The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities

Neurotrophin Pathway Receptors NGFR and TrkA Control Perineural Invasion, Metastasis, and Pain in Oral Cancer

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