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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Induction of pro-inflammatory cytokines by 29-kDa FN-f via cGAS/STING pathway

  • Hwang, Hyun Sook (Division of Rheumatology, Department of Internal Medicine, Hallym University Sacred Heart Hospital) ;
  • Lee, Mi Hyun (Division of Rheumatology, Department of Internal Medicine, Hallym University Sacred Heart Hospital) ;
  • Choi, Min Ha (Division of Rheumatology, Department of Internal Medicine, Hallym University Sacred Heart Hospital) ;
  • Kim, Hyun Ah (Division of Rheumatology, Department of Internal Medicine, Hallym University Sacred Heart Hospital)
  • Received : 2019.03.15
  • Accepted : 2019.04.08
  • Published : 2019.05.31
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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 granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF-2), granulocyte colony-stimulating factor (G-CSF/CSF-3), and type I interferon ($IFN-{\alpha}$), 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 $IFN-{\alpha}$ together with the decreased activation of TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), and inhibitor protein ${\kappa}B{\alpha}$ ($I{\kappa}B{\alpha}$). Furthermore, NOD2 or TLR-2 knockdown suppressed the expression of GM-CSF, G-CSF, and $IFN-{\alpha}$ 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.

Keywords

References

  1. Goldring MB (2000) The role of the chondrocyte in osteoarthritis. Arthritis Rheum 43, 1916-1926 https://doi.org/10.1002/1529-0131(200009)43:9<1916::AID-ANR2>3.0.CO;2-I
  2. Goldring MB and Goldring SR (2007) Osteoarthritis. J Cell Physiol 213, 626-634 https://doi.org/10.1002/jcp.21258
  3. Goldring SR and Goldring MB (2004) The role of cytokines in cartilage matrix degeneration in osteoarthritis. Clin Orthop Relat Res, S27-36
  4. Rosenberg JH, Rai V, Dilisio MF and Agrawal DK (2017) Damage-associated molecular patterns in the pathogenesis of osteoarthritis: potentially novel therapeutic targets. Mol Cell Biochem 434, 171-179 https://doi.org/10.1007/s11010-017-3047-4
  5. Rosenberg JH, Rai V, Dilisio MF, Sekundiak TD and Agrawal DK (2017) Increased expression of damageassociated molecular patterns (DAMPs) in osteoarthritis of human knee joint compared to hip joint. Mol Cell Biochem 436, 59-69 https://doi.org/10.1007/s11010-017-3078-x
  6. Hwang HS, Park SJ, Cheon EJ, Lee MH and Kim HA (2015) Fibronectin fragment-induced expression of matrix metalloproteinases is mediated by MyD88-dependent TLR-2 signaling pathway in human chondrocytes. Arthritis Res Ther 17, 320 https://doi.org/10.1186/s13075-015-0833-9
  7. Hwang HS, Lee MH and Kim HA (2019) Fibronectin fragment inhibits xylosyltransferase-1 expression by regulating Sp1/Sp3-dependent transcription in articular chondrocytes. Osteoarthritis Cartilage 27, 833-843 https://doi.org/10.1016/j.joca.2019.01.006
  8. Kim HA, Cho ML, Choi HY et al (2006) The catabolic pathway mediated by Toll-like receptors in human osteoarthritic chondrocytes. Arthritis Rheum 54, 2152-2163 https://doi.org/10.1002/art.21951
  9. Bobacz K, Sunk IG, Hofstaetter JG et al (2007) 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, 1880-1893 https://doi.org/10.1002/art.22637
  10. Xiao TS and Fitzgerald KA (2013) The cGAS-STING pathway for DNA sensing. Mol Cell 51, 135-139 https://doi.org/10.1016/j.molcel.2013.07.004
  11. Bai J, Cervantes C, Liu J et al (2017) 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, 12196-12201 https://doi.org/10.1073/pnas.1708744114
  12. Li T and Chen ZJ (2018) The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J Exp Med 215, 1287-1299 https://doi.org/10.1084/jem.20180139
  13. Dou Z, Ghosh K, Vizioli MG et al (2017) Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402-406 https://doi.org/10.1038/nature24050
  14. Kawai T and Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637-650 https://doi.org/10.1016/j.immuni.2011.05.006
  15. Chen AF, Davies CM, De Lin M and Fermor B (2008) Oxidative DNA damage in osteoarthritic porcine articular cartilage. J Cell Physiol 217, 828-833 https://doi.org/10.1002/jcp.21562
  16. Grishko VI, Ho R, Wilson GL and Pearsall AWt (2009) Diminished mitochondrial DNA integrity and repair capacity in OA chondrocytes. Osteoarthritis Cartilage 17, 107-113 https://doi.org/10.1016/j.joca.2008.05.009
  17. Barber GN (2015) STING: infection, inflammation and cancer. Nat Rev Immunol 15, 760-770 https://doi.org/10.1038/nri3921
  18. Ma Z and Damania B (2016) The cGAS-STING Defense Pathway and Its Counteraction by Viruses. Cell Host Microbe 19, 150-158 https://doi.org/10.1016/j.chom.2016.01.010
  19. Medzhitov R (2007) TLR-mediated innate immune recognition. Semin Immunol 19, 1-2 https://doi.org/10.1016/j.smim.2007.02.001
  20. Brubaker SW, Bonham KS, Zanoni I and Kagan JC (2015) Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol 33, 257-290 https://doi.org/10.1146/annurev-immunol-032414-112240
  21. Heinhuis B, Koenders MI, van de Loo FA et al (2010) 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, 1866-1872 https://doi.org/10.1136/ard.2009.127399
  22. Hwang HS, Lee MH, Choi MH and Kim HA (2019) NOD2 signaling pathway is involved in fibronectin fragment-induced pro-catabolic factor expressions in human articular chondrocytes. BMB Rep [Epub ahead of print]
  23. Joosten LA, Heinhuis B, Abdollahi-Roodsaz S et al (2008) Differential function of the NACHT-LRR (NLR) members Nod1 and Nod2 in arthritis. Proc Natl Acad Sci U S A 105, 9017-9022 https://doi.org/10.1073/pnas.0710445105
  24. Vieira SM, Cunha TM, Franca RF et al (2012) Joint NOD2/RIPK2 signaling regulates IL-17 axis and contributes to the development of experimental arthritis. J Immunol 188, 5116-5122 https://doi.org/10.4049/jimmunol.1004190
  25. Sun L, Wu J, Du F, Chen X and Chen ZJ (2013) Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786-791 https://doi.org/10.1126/science.1232458
  26. Crow YJ (2015) Type I interferonopathies: mendelian type I interferon up-regulation. Curr Opin Immunol 32, 7-12 https://doi.org/10.1016/j.coi.2014.10.005
  27. Kawane K, Ohtani M, Miwa K et al (2006) Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443, 998-1002 https://doi.org/10.1038/nature05245
  28. Lan YY, Londono D, Bouley R, Rooney MS and Hacohen N (2014) Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy. Cell Rep 9, 180-192 https://doi.org/10.1016/j.celrep.2014.08.074
  29. Ahn J, Gutman D, Saijo S and Barber GN (2012) STING manifests self DNA-dependent inflammatory disease. Proc Natl Acad Sci U S A 109, 19386-19391 https://doi.org/10.1073/pnas.1215006109
  30. Kim HA, Lee YJ, Seong SC, Choe KW and Song YW (2000) Apoptotic chondrocyte death in human osteoarthritis. J Rheumatol 27, 455-462
  31. Kim J, Xu M, Xo R et al (2010) Mitochondrial DNA damage is involved in apoptosis caused by proinflammatory cytokines in human OA chondrocytes. Osteoarthritis Cartilage 18, 424-432 https://doi.org/10.1016/j.joca.2009.09.008
  32. Leizer T, Cebon J, Layton JE and Hamilton JA (1990) 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, 1989-1996 https://doi.org/10.1182/blood.V76.10.1989.1989
  33. Hamilton JA, Filonzi EL and Ianches G (1993) Regulation of macrophage colony-stimulating factor (M-CSF) production in cultured human synovial fibroblasts. Growth Factors 9, 157-165 https://doi.org/10.3109/08977199309010831
  34. Campbell IK, Novak U, Cebon J, Layton JE and Hamilton JA (1991) Human articular cartilage and chondrocytes produce hemopoietic colony-stimulating factors in culture in response to IL-1. J Immunol 147, 1238-1246
  35. Campbell IK, Ianches G and Hamilton JA (1993) 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, 57-63 https://doi.org/10.1016/0925-4439(93)90153-R
  36. Achuthan A, Cook AD, Lee MC et al (2016) Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation. J Clin Invest 126, 3453-3466 https://doi.org/10.1172/JCI87828
  37. Lee MC, Saleh R, Achuthan A et al (2018) CCL17 blockade as a therapy for osteoarthritis pain and disease. Arthritis Res Ther 20, 62 https://doi.org/10.1186/s13075-018-1560-9
  38. Cook AD, Pobjoy J, Steidl S et al (2012) Granulocytemacrophage colony-stimulating factor is a key mediator in experimental osteoarthritis pain and disease development. Arthritis Res Ther 14, R199 https://doi.org/10.1186/ar4037
  39. Cook AD, Pobjoy J, Sarros S et al (2013) Granulocytemacrophage colony-stimulating factor is a key mediator in inflammatory and arthritic pain. Ann Rheum Dis 72, 265-270 https://doi.org/10.1136/annrheumdis-2012-201703
  40. Yang YH and Hamilton JA (2001) Dependence of interleukin-1-induced arthritis on granulocyte-macrophage colony-stimulating factor. Arthritis Rheum 44, 111-119 https://doi.org/10.1002/1529-0131(200101)44:1<111::AID-ANR15>3.0.CO;2-1
  41. Miller JC, Ma Y, Bian J et al (2008) A critical role for type I IFN in arthritis development following Borrelia burgdorferi infection of mice. J Immunol 181, 8492-8503 https://doi.org/10.4049/jimmunol.181.12.8492
  42. Roelofs MF, Wenink MH, Brentano F et al (2009) Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4-mediated synovial inflammation in rheumatoid arthritis (RA). Ann Rheum Dis 68, 1486-1493 https://doi.org/10.1136/ard.2007.086421
  43. Triantaphyllopoulos KA, Williams RO, Tailor H and Chernajovsky Y (1999) 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, 90-99 https://doi.org/10.1002/1529-0131(199901)42:1<90::AID-ANR12>3.0.CO;2-A
  44. Wong T, Majchrzak B, Bogoch E, Keystone EC and Fish EN (2003) Therapeutic implications for interferon-alpha in arthritis: a pilot study. J Rheumatol 30, 934-940
  45. Burdette DL and Vance RE (2013) STING and the innate immune response to nucleic acids in the cytosol. Nat Immunol 14, 19-26 https://doi.org/10.1038/ni.2491