STING promotes senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the NF-κB signaling pathway

Cell Death and Disease - Tập 12 Số 1
Qiang Guo1, Ximiao Chen1, Jiaoxiang Chen1, Gang Zheng1, Chenglong Xie1, Hongqiang Wu1, Zhimin Miao1, Yan Lin1, Xiangyang Wang2, Weiyang Gao2, Xiangtao Zheng3, Zongyou Pan4, Yifei Zhou1, Yaosen Wu1, Xiaolei Zhang1
1Department of Orthopedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China
2Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, 325000, Zhejiang Province, China
3Department of Vascular Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China
4Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, Zhejiang Province, China

Tóm tắt

AbstractDamaged deoxyribonucleic acid (DNA) is a primary pathologic factor for osteoarthritis (OA); however, the mechanism by which DNA damage drives OA is unclear. Previous research demonstrated that the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) participates in DNA damage response. As a result, the current study aimed at exploring the role STING, which is the major effector in the cGAS-STING signaling casacde, in OA progress in vitro, as well as in vivo. In this study, the expression of STING was evaluated in the human and mouse OA tissues, and in chondrocytes exposed to interleukin-1 beta (IL-1β). The influences of STING on the metabolism of the extracellular matrix (ECM), apoptosis, and senescence, were assessed in STING overexpressing and knocking-down chondrocytes. Moreover, the NF-κB-signaling casacde and its role in the regulatory effects of STING on ECM metabolism, apoptosis, and senescence were explored. The STING knockdown lentivirus was intra-articularly injected to evaluate its therapeutic impact on OA in mice in vivo. The results showed that the expression of STING was remarkably elevated in the human and mouse OA tissues and in chondrocytes exposed to IL-1β. Overexpression of STING promoted the expression of MMP13, as well as ADAMTS5, but suppressed the expression of Aggrecan, as well as Collagen II; it also enhanced apoptosis and senescence in chondrocytes exposed to and those untreated with IL-1β. The mechanistic study showed that STING activated NF-κB signaling cascade, whereas the blockage of NF-κB signaling attenuated STING-induced apoptosis and senescence, and ameliorated STING-induced ECM metabolism imbalance. In in vivo study, it was demonstrated that STING knockdown alleviated destabilization of the medial meniscus-induced OA development in mice. In conclusion, STING promotes OA by activating the NF-κB signaling cascade, whereas suppression of STING may provide a novel approach for OA therapy.

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Tài liệu tham khảo

Lane, N., Shidara, K. & Wise, B. Osteoarthritis year in review 2016: clinical. Osteoarthr. Cartil. 25, 209–215 (2017).

Blagojevic, M., Jinks, C., Jeffery, A. & Jordan, K. Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthr. Cartil. 18, 24–33 (2010).

Tateiwa, D., Yoshikawa, H. & Kaito, T. Cartilage and bone destruction in arthritis: pathogenesis and treatment strategy: a literature review. Cells 8, 818 (2019).

Ge, Z. et al. Osteoarthritis and therapy. Arthritis Rheum. 55, 493–500 (2006).

Héraud, F., Héraud, A. & Harmand, M. Apoptosis in normal and osteoarthritic human articular cartilage. Ann. Rheum. Dis. 59, 959–965 (2000).

Burdak-Rothkamm, S., Mansour, W. & Rothkamm, K. DNA damage repair deficiency in prostate cancer. Trends Cancer 6, 974–984 (2020).

Tiwari, V. & Wilson, D. DNA damage and associated DNA repair defects in disease and premature aging. Am. J. Hum. Genet. 105, 237–257 (2019).

Kim, J. et al. Mitochondrial DNA damage is involved in apoptosis caused by pro-inflammatory cytokines in human OA chondrocytes. Osteoarthr. Cartil. 18, 424–432 (2010).

Davies, C., Guilak, F., Weinberg, J. & Fermor, B. Reactive nitrogen and oxygen species in interleukin-1-mediated DNA damage associated with osteoarthritis. Osteoarthr. Cartil. 16, 624–630 (2008).

Alvarez-Garcia, O. et al. Regulated in development and DNA damage response 1 deficiency impairs autophagy and mitochondrial biogenesis in articular cartilage and increases the severity of experimental osteoarthritis. Arthritis Rheumatol. 69, 1418–1428 (2017).

Hopfner, K. & Hornung, V. Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat. Rev. Mol. Cell Biol. 21, 501–521 (2020).

Su, C. et al. DNA-induced 2'3’-cGAMP enhances haplotype-specific human STING cleavage by dengue protease. Proc. Natl. Acad. Sci. USA 117, 15947–15954 (2020).

von Roemeling, C. et al. Therapeutic modulation of phagocytosis in glioblastoma can activate both innate and adaptive antitumour immunity. Nat. Commun. 11, 1508 (2020).

Kwon, J. & Bakhoum, S. The cytosolic DNA-sensing cGAS-STING pathway in cancer. Cancer Discov. 10, 26–39 (2020).

Jauhari, A. et al. Melatonin inhibits cytosolic mitochondrial DNA-induced neuroinflammatory signaling in accelerated aging and neurodegeneration. J. Clin. Investig. 130, 3124–3136 (2020).

Vizioli, M. et al. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes Dev. 34, 428–445 (2020).

Tang, C. et al. Agonist-mediated activation of STING induces apoptosis in malignant B cells. Cancer Res. 76, 2137–2152 (2016).

Park, C. et al. Sargassum serratifolium extract attenuates interleukin-1β-induced oxidative stress and inflammatory response in chondrocytes by suppressing the activation of NF-κB, p38 MAPK, and PI3K/Akt. Int. J. Mol. Sci. 19, https://doi.org/10.3390/ijms19082308 (2018).

Balka, K. et al. TBK1 and IKKε Act redundantly to mediate STING-induced NF-κB responses in myeloid cells. Cell Rep. 31, 107492 (2020).

Kang, D. et al. Stress-activated miR-204 governs senescent phenotypes of chondrocytes to promote osteoarthritis development. Sci. Transl. Med. 11, eaar6659 (2019).

Varela-Eirin, M. et al. Cartilage regeneration and ageing: targeting cellular plasticity in osteoarthritis. Ageing Res. Rev. 42, 56–71 (2018).

Pattacini, L. et al. Angiotensin II protects fibroblast-like synoviocytes from apoptosis via the AT1-NF-kappaB pathway. Rheumatol. (Oxf., Engl.) 46, 1252–1257 (2007).

El Maï, M., Marzullo, M., de Castro, I. & Ferreira, M. Opposing p53 and mTOR/AKT promote an in vivo switch from apoptosis to senescence upon telomere shortening in zebrafish. eLife 9, e54935 (2020).

Shmulevich, R. & Krizhanovsky, V. Cell senescence, DNA damage, and metabolism. Antioxid. Redox Signal. https://doi.org/10.1089/ars.2020.8043 (2020).

Onuora, S. Osteoarthritis: OA chondrocytes made senescent by genomic DNA damage. Nature reviews. Rheumatology 8, 502 (2012).

Simelyte, E., Boyle, D. & Firestein, G. DNA mismatch repair enzyme expression in synovial tissue. Ann. Rheum. Dis. 63, 1695–1699 (2004).

Song, X., Ma, F. & Herrup, K. Accumulation of cytoplasmic DNA due to ATM deficiency activates the microglial viral response system with neurotoxic consequences. J. Neurosci. 39, 6378–6394 (2019).

Gekara, N. DNA damage-induced immune response: micronuclei provide key platform. J. Cell Biol. 216, 2999–3001 (2017).

Ahn, J., Gutman, D., Saijo, S. & Barber, G. STING manifests self DNA-dependent inflammatory disease. Proc. Natl. Acad. Sci. USA 109, 19386–19391 (2012).

Aarreberg, L. et al. Interleukin-1β induces mtDNA release to activate innate immune signaling via cGAS-STING. Mol. Cell 74, 801–815.e806 (2019).

Yang, H., Wang, H., Ren, J., Chen, Q. & Chen, Z. cGAS is essential for cellular senescence. Proc. Natl. Acad. Sci. USA 114, E4612–E4620 (2017).

Glück, S. et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 19, 1061–1070 (2017).

Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017).

Gulen, M. et al. Signalling strength determines proapoptotic functions of STING. Nat. Commun. 8, 427 (2017).

Rahmati, M., Nalesso, G., Mobasheri, A. & Mozafari, M. Aging and osteoarthritis: central role of the extracellular matrix. Ageing Res. Rev. 40, 20–30 (2017).

Choi, M., Jo, J., Park, J., Kang, H. & Park, Y. NF-κB signaling pathways in osteoarthritic cartilage destruction. Cells 8, 734 (2019).

Lepetsos, P., Papavassiliou, K. & Papavassiliou, A. Redox and NF-κB signaling in osteoarthritis. Free Radic. Biol. Med. 132, 90–100 (2019).

Yan, H. et al. Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury. Proc. Natl. Acad. Sci. USA 113, E6199–E6208 (2016).

Montaseri, A. et al. IGF-1 and PDGF-bb suppress IL-1β-induced cartilage degradation through down-regulation of NF-κB signaling: involvement of Src/PI-3K/AKT pathway. PloS ONE 6, e28663 (2011).

Arepalli, S., Choi, M., Jung, J. & Lee, H. Novel NF-κB inhibitors: a patent review (2011 - 2014). Expert Opin. Ther. Pat. 25, 319–334 (2015).

Gilmore, T. & Herscovitch, M. Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene 25, 6887–6899 (2006).

Saklatvala, J. Inflammatory signaling in cartilage: MAPK and NF-kappaB pathways in chondrocytes and the use of inhibitors for research into pathogenesis and therapy of osteoarthritis. Curr. Drug targets 8, 305–313 (2007).

Haag, S. et al. Targeting STING with covalent small-molecule inhibitors. Nature 559, 269–273 (2018).

Vincent, J. et al. Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice. Nat. Commun. 8, 750 (2017).

Shimizu, I., Yoshida, Y., Suda, M. & Minamino, T. DNA damage response and metabolic disease. Cell Metab. 20, 967–977 (2014).

Takahashi, A. et al. Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells. Nat. Commun. 9, 1249 (2018).

Glasson, S., Blanchet, T. & Morris, E. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthr. Cartil. 15, 1061–1069 (2007).

Kraus, V., Huebner, J., DeGroot, J. & Bendele, A. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the guinea pig. Osteoar. Cartil. S35-S52, https://doi.org/10.1016/j.joca.2010.04.015 (2010).

Lewis, J. et al. Acute joint pathology and synovial inflammation is associated with increased intra-articular fracture severity in the mouse knee. Osteoarthr. Cartil. 19, 864–873 (2011).

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Cell Death and Disease

Tập 12 Số 1

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