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Induction of pro-inflammatory cytokines by 29-kDa FN-f via cGAS/STING pathway

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The cGAS-STING pathway plays an important role in pathogen-induced activation of the innate immune response. The 29-kDa amino-terminal fibronectin fragment (29-kDa FN-f) found predominantly in the synovial fluid of osteoarthritis (OA) patients increases the expression of catabolic factors via the toll-like receptor-2 (TLR-2) signaling pathway. In this study, we investigated whether 29-kDa FN-f induces inflammatory responses via the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) pathway in human primary chondrocytes. The levels of cGAS and STING were elevated in OA cartilage compared with normal cartilage. Long-term treatment of chondrocytes with 29-kDa FN-f activated the cGAS/STING pathway together with the increased level of gamma-H2AX, a marker of DNA breaks. In addition, the expression of pro-inflammatory cytokines, including granulocytemacrophage colony-stimulating factor (GM-CSF/CSF-2), granulocyte colony-stimulating factor (G-CSF/CSF-3), and type I interferon (IFN-), was increased more than 100-fold in 29-kDa FN-f-treated chondrocytes. However, knockdown of cGAS and STING suppressed 29-kDa FN-f-induced expression of GM-CSF, G-CSF, and IFN- together with the decreased activation of TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), and inhibitor protein B (IB). Furthermore, NOD2 or TLR-2 knockdown suppressed the expression of GM-CSF, G-CSF, and IFN- as well as decreased the activation of the cGAS/STING pathway in 29-kDa FN-f-treated chondrocytes. These data demonstrate that the cGAS/STING/TBK1/IRF3 pathway plays a critical role in 29-kDa FN-f-induced expression of pro-inflammatory cytokines.

Abstract

The cGAS-STING pathway plays an important role in pathogen-induced activation of the innate immune response. The 29-kDa amino-terminal fibronectin fragment (29-kDa FN-f) found predominantly in the synovial fluid of osteoarthritis (OA) patients increases the expression of catabolic factors via the toll-like receptor-2 (TLR-2) signaling pathway. In this study, we investigated whether 29-kDa FN-f induces inflammatory responses via the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) pathway in human primary chondrocytes. The levels of cGAS and STING were elevated in OA cartilage compared with normal cartilage. Long-term treatment of chondrocytes with 29-kDa FN-f activated the cGAS/STING pathway together with the increased level of gamma-H2AX, a marker of DNA breaks. In addition, the expression of pro-inflammatory cytokines, including granulocytemacrophage colony-stimulating factor (GM-CSF/CSF-2), granulocyte colony-stimulating factor (G-CSF/CSF-3), and type I interferon (IFN-), was increased more than 100-fold in 29-kDa FN-f-treated chondrocytes. However, knockdown of cGAS and STING suppressed 29-kDa FN-f-induced expression of GM-CSF, G-CSF, and IFN- together with the decreased activation of TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), and inhibitor protein B (IB). Furthermore, NOD2 or TLR-2 knockdown suppressed the expression of GM-CSF, G-CSF, and IFN- as well as decreased the activation of the cGAS/STING pathway in 29-kDa FN-f-treated chondrocytes. These data demonstrate that the cGAS/STING/TBK1/IRF3 pathway plays a critical role in 29-kDa FN-f-induced expression of pro-inflammatory cytokines.

참고문헌 (45)

  1. Goldring MB, "The role of the chondrocyte in osteoarthritis", Arthritis Rheum, 43, pp.1916~1926 (2000)
  2. Goldring MB, "Osteoarthritis", J Cell Physiol, 213, pp.626~634 (2007)
  3. Goldring SR, "The role of cytokines in cartilage matrix degeneration in osteoarthritis", Clin Orthop Relat Res, pp.S27~S36 (2004)
  4. Rosenberg JH, "Damage-associated molecular patterns in the pathogenesis of osteoarthritis : potentially novel therapeutic targets", Mol Cell Biochem, 434, pp.171~179 (2017)
  5. Rosenberg JH, "Increased expression of damageassociated molecular patterns(DAMPs)in osteoarthritis of human knee joint compared to hip joint", Mol Cell Biochem, 436, pp.59~69 (2017)
  6. Hwang HS, "Fibronectin fragment-induced expression of matrix metalloproteinases is mediated by MyD88-dependent TLR-2 signaling pathway in human chondrocytes", Arthritis Res Ther, 17, pp.320~ (2015)
  7. Hwang HS, "Fibronectin fragment inhibits xylosyltransferase-1 expression by regulating Sp1", Sp3-dependent transcription in articular chondrocytes, 2019, pp.27, 833~843
  8. Kim HA, "The catabolic pathway mediated by Toll-like receptors in human osteoarthritic chondrocytes", Arthritis Rheum, 54, pp.2152~2163 (2006)
  9. Bobacz K, "Toll-like receptors and chondrocytes : the lipopolysaccharideinduced decrease in cartilage matrix synthesis is dependent on the presence of toll-like receptor 4 and antagonized by bone morphogenetic protein 7", Arthritis Rheum, 56, pp.1880~1893 (2007)
  10. Xiao TS, "The cGAS-STING pathway for DNA sensing", Mol Cell, 51, pp.135~139 (2013)
  11. Bai J, "DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMPSTING pathway", Proc Natl Acad Sci U S A, 114, pp.12196~12201 (2017)
  12. Li T, "The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer", J Exp Med, 215, pp.1287~1299 (2018)
  13. Dou Z, "Cytoplasmic chromatin triggers inflammation in senescence and cancer", Nature, 550, pp.402~406 (2017)
  14. Kawai T, "Toll-like receptors and their crosstalk with other innate receptors in infection and immunity", Immunity, 34, pp.637~650 (2011)
  15. Chen AF, "Oxidative DNA damage in osteoarthritic porcine articular cartilage", J Cell Physiol, 217, pp.828~833 (2008)
  16. Grishko VI, "Diminished mitochondrial DNA integrity and repair capacity in OA chondrocytes", Osteoarthritis Cartilage, 17, pp.107~113 (2009)
  17. Barber GN, "STING : infection, inflammation and cancer", Nat Rev Immunol, 15, pp.760~770 (2015)
  18. Ma Z, "The cGAS-STING Defense Pathway and Its Counteraction by Viruses", Cell Host Microbe, 19, pp.150~158 (2016)
  19. Medzhitov R, "TLR-mediated innate immune recognition", Semin Immunol, 19, pp.1~2 (2007)
  20. Brubaker SW, "Innate immune pattern recognition : a cell biological perspective", Annu Rev Immunol, 33, pp.257~290 (2015)
  21. Heinhuis B, "IL-32gamma and Streptococcus pyogenes cell wall fragments synergise for IL-1-dependent destructive arthritis via upregulation of TLR-2 and NOD2", Ann Rheum Dis, 69, pp.1866~1872 (2010)
  22. 황현숙, "NOD2 signaling pathway is involved in fibronectin fragment-induced pro-catabolic factor expressions in human articular chondrocytes", BMB Reports, 52(6), pp.373~378 (2019), 생화학분자생물학회[DOI]
  23. Joosten LA, "Differential function of the NACHT-LRR(NLR)members Nod1 and Nod2 in arthritis", Proc Natl Acad Sci U S A, 105, pp.9017~9022 (2008)
  24. Vieira SM, "Joint NOD2", RIPK2 signaling regulates IL-17 axis and contributes to the development of experimental arthritis, 2012, pp.188, 5116~5122
  25. Sun L, "Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway", Science, 339, pp.786~791 (2013)
  26. Crow YJ, "Type I interferonopathies : mendelian type I interferon up-regulation", Curr Opin Immunol, 32, pp.7~12 (2015)
  27. Kawane K, "Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages", Nature, 443, pp.998~1002 (2006)
  28. Lan YY, "Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy", Cell Rep, 9, pp.180~192 (2014)
  29. Ahn J, "STING manifests self DNA-dependent inflammatory disease", Proc Natl Acad Sci U S A, 109, pp.19386~19391 (2012)
  30. Kim HA, "Apoptotic chondrocyte death in human osteoarthritis", J Rheumatol, 27, pp.455~462 (2000)
  31. Kim J, "Mitochondrial DNA damage is involved in apoptosis caused by proinflammatory cytokines in human OA chondrocytes", Osteoarthritis Cartilage, 18, pp.424~432 (2010)
  32. Leizer T, "Cytokine regulation of colony-stimulating factor production in cultured human synovial fibroblasts : I. Induction of GM-CSF and G-CSF production by interleukin-1 and tumor necrosis factor", Blood, 76, pp.1989~1996 (1990)
  33. Hamilton JA, "Regulation of macrophage colony-stimulating factor(M-CSF)production in cultured human synovial fibroblasts", Growth Factors, 9, pp.157~165 (1993)
  34. Campbell IK, "Human articular cartilage and chondrocytes produce hemopoietic colony-stimulating factors in culture in response to IL-1", J Immunol, 147, pp.1238~1246 (1991)
  35. Campbell IK, "Production of macrophage colony-stimulating factor(M-CSF)by human articular cartilage and chondrocytes. Modulation by interleukin-1 and tumor necrosis factor alpha", Biochim Biophys Acta, 1182, pp.57~63 (1993)
  36. Achuthan A, "Granulocyte macrophage colony-stimulating factor induces CCL17production via IRF4 to mediate inflammation", J Clin Invest, 126, pp.3453~3466 (2016)
  37. Lee MC, "CCL17blockade as a therapy for osteoarthritis pain and disease", Arthritis Res Ther, 20, pp.62~ (2018)
  38. Cook AD, "Granulocytemacrophage colony-stimulating factor is a key mediator in experimental osteoarthritis pain and disease development", Arthritis Res Ther, 14, pp.R199~ (2012)
  39. Cook AD, "Granulocytemacrophage colony-stimulating factor is a key mediator in inflammatory and arthritic pain", Ann Rheum Dis, 72, pp.265~270 (2013)
  40. Yang YH, "Dependence of interleukin-1-induced arthritis on granulocyte-macrophage colony-stimulating factor", Arthritis Rheum, 44, pp.111~119 (2001)
  41. Miller JC, "A critical role for type I IFN in arthritis development following Borrelia burgdorferi infection of mice", J Immunol, 181, pp.8492~8503 (2008)
  42. Roelofs MF, "Type I interferons might form the link between Toll-like receptor(TLR)3", 7 and TLR4-mediated synovial inflammation in rheumatoid arthritis(RA), 2009, pp.68, 1486~1493
  43. Triantaphyllopoulos KA, "Amelioration of collagen-induced arthritis and suppression of interferon-gamma, interleukin-12, and tumor necrosis factor alpha production by interferon-beta gene therapy", Arthritis Rheum, 42, pp.90~99 (1999)
  44. Wong T, "Therapeutic implications for interferon-alpha in arthritis : a pilot study", J Rheumatol, 30, pp.934~940 (2003)
  45. Burdette DL, "STING and the innate immune response to nucleic acids in the cytosol", Nat Immunol, 14, pp.19~26 (2013)

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NOD2 signaling pathway is involved in fibronectin fragment-induced pro-catabolic factor expressions in human articular chondrocytes김현아, 이미현, 최민하, 황현숙생화학분자생물학회 · BMB Reports2019 · 제52권 제6호29-kDa FN-f inhibited autophagy through modulating localization of HMGB1 in human articular chondrocytes김현아, 최민하, 황현숙생화학분자생물학회 · BMB Reports2018 · 제51권 제10호Cytosolic escape of mitochondrial DNA triggers cGAS-STING-NLRP3 axis-dependent nucleus pulposus cell pyroptosisFeng Xiaobo, Hua Wenbin, Ke Wencan, Lei Jie, Liao Zhiwei, Li Gaocai, Liu Hui, Luo Rongjin, Ma Liang, Song Yu, Wang Bingjin, Wang Kun, Wu Xinghuo, Yang Cao, Zhang Weifeng, Zhang Yukun, Zhao Kangcheng생화학분자생물학회 · Experimental and Molecular Medicine2022 · 제54권 Engagement of Toll-Like Receptor 3 Induces Vascular Endothelial Growth Factor and Interleukin-8 in Human Rheumatoid Synovial Fibroblasts곽승기, 김호연, 문수진, 박경수, 박미경, 박성환, 오혜좌, 이선영, 조미라, 주지현대한내과학회 · The Korean Journal of Internal Medicine2010 · 제25권 제4호Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathwayChung Jay H., Kim Ho-Shik, Kim Jeonghan생화학분자생물학회 · Experimental and Molecular Medicine2023 · 제55권 Glucosamine Inhibits Lipopolysaccharide-induced Inflammatory Responses in Human Periodontal Ligament Fibroblasts김은담, 박현정, 백정화대한구강생물학회 · International Journal of Oral Biology2014 · 제39권 제4호

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