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Inflammation Research

Erschienen in:

26.03.2018 | Review

Inflammation, a significant player of Ataxia–Telangiectasia pathogenesis?

verfasst von: Majid Zaki-Dizaji, Seyed Mohammad Akrami, Gholamreza Azizi, Hassan Abolhassani, Asghar Aghamohammadi

Erschienen in: Inflammation Research | Ausgabe 7/2018

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Abstract

Introduction

Ataxia–Telangiectasia (A-T) syndrome is an autosomal recessive neurodegenerative disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, chromosome instability, radiosensitivity, and predisposition to malignancy. There is growing evidence that A–T patients suffer from pathologic inflammation that is responsible for many symptoms of this syndrome, including neurodegeneration, autoimmunity, cardiovascular disease, accelerated aging, and insulin resistance. In addition, epidemiological studies have shown A–T heterozygotes, somewhat like deficient patients, are susceptible to ionizing irradiation and have a higher risk of cancers and metabolic disorders.

Area covered

This review summarizes clinical and molecular findings of inflammation in A–T syndrome.

Conclusion

Ataxia–Telangiectasia Mutated (ATM), a master regulator of the DNA damage response is the protein known to be associated with A–T and has a complex nuclear and cytoplasmic role. Loss of ATM function may induce immune deregulation and systemic inflammation.

Zaki Dizaji M, Akrami SM, Abolhassani H, Rezaei N, Aghamohammadi A. Ataxia telangiectasia syndrome: moonlighting ATM. Expert Rev Clin Immunol. 2017;13(12):1155–72. https://doi.org/10.1080/1744666X.2017.1392856.PubMedCrossRef

Chun HH, Gatti RA. Ataxia–telangiectasia, an evolving phenotype. DNA Repair. 2004;3(8):1187–96.PubMedCrossRef

Dizaji MZ, Rezaei N, Yaghmaie M, Yaseri M, Sayedi SJ, Azizi G, et al. Phospho-SMC1 in-cell ELISA based detection of ataxia telangiectasia. Int J Pediatr Massha. 2016;4(12):3957–67. https://doi.org/10.22038/ijp.2016.7751.CrossRef

Driessen GJ, Ijspeert H, Weemaes CM, Haraldsson A, Trip M, Warris A, et al. Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity. J Allergy Clin Immunol. 2013;131(5):1367 e9–75 e9. https://doi.org/10.1016/j.jaci.2013.01.053.CrossRef

Moin M, Aghamohammadi A, Kouhi A, Tavassoli S, Rezaei N, Ghaffari SR, et al. Ataxia-telangiectasia in Iran: clinical and laboratory features of 104 patients. Pediatr Neurol. 2007;37(1):21–8. https://doi.org/10.1016/j.pediatrneurol.2007.03.002.PubMedCrossRef

Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM. Immunodeficiency and infections in ataxia-telangiectasia. J Pediatr. 2004;144(4):505–11. https://doi.org/10.1016/j.jpeds.2003.12.046.PubMedCrossRef

Kraus M, Lev A, Simon AJ, Levran I, Nissenkorn A, Levi YB, et al. Disturbed B and T cell homeostasis and neogenesis in patients with ataxia telangiectasia. J Clin Immunol. 2014;34(5):561–72. https://doi.org/10.1007/s10875-014-0044-1.PubMedCrossRef

Ghiasy S, Parvaneh L, Azizi G, Sadri G, Zaki Dizaji M, Abolhassani H, et al. The clinical significance of complete class switching defect in ataxia telangiectasia patients. Expert Rev Clin Immunol. 2017;13(5):499–505. https://doi.org/10.1080/1744666X.2017.1292131.PubMedCrossRef

Chopra C, Davies G, Taylor M, Anderson M, Bainbridge S, Tighe P, et al. Immune deficiency in Ataxia–Telangiectasia: a longitudinal study of 44 patients. Clin Exp Immunol. 2014;176(2):275–82. https://doi.org/10.1111/cei.12262.PubMedPubMedCentralCrossRef

10.

Bredemeyer AL, Huang CY, Walker LM, Bassing CH, Sleckman BP. Aberrant V(D)J recombination in ataxia telangiectasia mutated-deficient lymphocytes is dependent on nonhomologous DNA end joining. J Immunol. 2008;181(4):2620–5.PubMedPubMedCentralCrossRef

11.

Lumsden JM, McCarty T, Petiniot LK, Shen R, Barlow C, Wynn TA, et al. Immunoglobulin class switch recombination is impaired in Atm-deficient mice. J Exp Med. 2004;200(9):1111–21.PubMedPubMedCentralCrossRef

12.

Pan-Hammarstrom Q, Dai S, Zhao Y, van Dijk-Hard IF, Gatti RA, Borresen-Dale AL, et al. ATM is not required in somatic hypermutation of VH, but is involved in the introduction of mutations in the switch mu region. J Immunol. 2003;170(7):3707–16.PubMedCrossRef

13.

Ammann AJ, Hong R. Autoimmune phenomena in ataxia telangiectasia. J Pediatr. 1971;78(5):821–6.PubMedCrossRef

14.

Kutukculer N, Aksu G. Is there an association between autoimmune hemolytic anemia and ataxia–telangiectasia? Autoimmunity. 2000;32(2):145–7.PubMedCrossRef

15.

Meyts I, Weemaes C, De Wolf-Peeters C, Proesmans M, Renard M, Uyttebroeck A, et al. Unusual and severe disease course in a child with ataxia–telangiectasia. Pediatr Allergy Immunol. 2003;14(4):330–3.PubMedCrossRef

16.

Heath J, Goldman FD. Idiopathic thrombocytopenic purpura in a boy with ataxia telangiectasia on immunoglobulin replacement therapy. J Pediatr Hematol Oncol. 2010;32(1):e25–7. https://doi.org/10.1097/MPH.0b013e3181bf29b6.PubMedCrossRef

17.

Sari A, Okuyaz C, Adiguzel U, Ates NA. Uncommon associations with ataxia–telangiectasia: vitiligo and optic disc drusen. Ophthalm Genet. 2009;30(1):19–22. https://doi.org/10.1080/13816810802415256.CrossRef

18.

Pasini AM, Gagro A, Roic G, Vrdoljak O, Lujic L, Zutelija-Fattorini M. Ataxia telangiectasia and juvenile idiopathic arthritis. Pediatrics. 2017. https://doi.org/10.1542/peds.2016-1279.PubMedCrossRef

19.

Shao L, Fujii H, Colmegna I, Oishi H, Goronzy JJ, Weyand CM. Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis. J Exp Med. 2009;206(6):1435–49. https://doi.org/10.1084/jem.20082251.PubMedPubMedCentralCrossRef

20.

Westbrook AM, Schiestl RH. Atm-deficient mice exhibit increased sensitivity to dextran sulfate sodium-induced colitis characterized by elevated DNA damage and persistent immune activation. Cancer Res. 2010;70(5):1875–84. https://doi.org/10.1158/0008-5472.CAN-09-2584.PubMedPubMedCentralCrossRef

21.

Deng X, Ljunggren-Rose A, Maas K, Sriram S. Defective. ATM-p53-mediated apoptotic pathway in multiple sclerosis. Ann Neurol. 2005;58(4):577–84. https://doi.org/10.1002/ana.20600.PubMedCrossRef

22.

Reichenbach J, Schubert R, Schindler D, Muller K, Bohles H, Zielen S. Elevated oxidative stress in patients with ataxia telangiectasia. Antioxid Redox Signal. 2002;4(3):465–9. https://doi.org/10.1089/15230860260196254.PubMedCrossRef

23.

Barzilai A, Rotman G, Shiloh Y. ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage. DNA Repair. 2002;1(1):3–25.PubMedCrossRef

24.

McKinnon PJ. ATM and ataxia telangiectasia. EMBO Rep. 2004;5(8):772–6. https://doi.org/10.1038/sj.embor.7400210.PubMedPubMedCentralCrossRef

25.

McGrath-Morrow SA, Collaco JM, Crawford TO, Carson KA, Lefton-Greif MA, Zeitlin P, et al. Elevated serum IL-8 levels in ataxia telangiectasia. J Pediatr. 2010;156(4):682.e1–684.e1. https://doi.org/10.1016/j.jpeds.2009.12.007.CrossRef

26.

McGrath-Morrow SA, Collaco JM, Detrick B, Lederman HM. Serum Interleukin-6 levels and pulmonary function in ataxia–telangiectasia. J Pediatr. 2016;171:256–61 e1. https://doi.org/10.1016/j.jpeds.2016.01.002.PubMedPubMedCentralCrossRef

27.

Privette ED, Ram G, Treat JR, Yan AC, Heimall JR. Healing of granulomatous skin changes in ataxia–telangiectasia after treatment with intravenous immunoglobulin and topical mometasone 0.1% ointment. Pediatr Dermatol. 2014;31(6):703–7. https://doi.org/10.1111/pde.12411.PubMedCrossRef

28.

Mitra A, Gooi J, Darling J, Newton-Bishop JA. Infliximab in the treatment of a child with cutaneous granulomas associated with ataxia telangiectasia. J Am Acad Dermatol. 2011;65(3):676–7. https://doi.org/10.1016/j.jaad.2010.06.060.PubMedCrossRef

29.

Chiam LY, Verhagen MM, Haraldsson A, Wulffraat N, Driessen GJ, Netea MG, et al. Cutaneous granulomas in ataxia telangiectasia and other primary immunodeficiencies: reflection of inappropriate immune regulation? Dermatology. 2011;223(1):13–9. https://doi.org/10.1159/000330335.PubMedCrossRef

30.

Paller AS, Massey RB, Curtis MA, Pelachyk JM, Dombrowski HC, Leickly FE, et al. Cutaneous granulomatous lesions in patients with ataxia–telangiectasia. J Pediatr. 1991;119(6):917–22.PubMedCrossRef

31.

Schroeder SA, Swift M, Sandoval C, Langston C. Interstitial lung disease in patients with ataxia–telangiectasia. Pediatr Pulmonol. 2005;39(6):537–43. https://doi.org/10.1002/ppul.20209.PubMedCrossRef

32.

Shoimer I, Wright N, Haber RM. Noninfectious Granulomas. A sign of an underlying immunodeficiency? J Cutan Med Surg. 2016;20(3):259–62. https://doi.org/10.1177/1203475415626085.PubMedCrossRef

33.

Erttmann SF, Hartlova A, Sloniecka M, Raffi FA, Hosseinzadeh A, Edgren T, et al. Loss of the DNA damage repair kinase ATM impairs inflammasome-dependent anti-bacterial innate immunity. Immunity. 2016;45(1):106–18. https://doi.org/10.1016/j.immuni.2016.06.018.PubMedCrossRef

34.

Hartlova A, Erttmann SF, Raffi FA, Schmalz AM, Resch U, Anugula S, et al. DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity. Immunity. 2015;42(2):332–43. https://doi.org/10.1016/j.immuni.2015.01.012.PubMedCrossRef

35.

Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer. 2003;3(3):155–68.PubMedCrossRef

36.

Ribezzo F, Shiloh Y, Schumacher B (eds) Systemic DNA damage responses in aging and diseases. Semin Cancer Biol; 2016

37.

Yang Y, Hui CW, Li J, Herrup K. The interaction of the atm genotype with inflammation and oxidative stress. PLoS One. 2014;9(1):e85863. https://doi.org/10.1371/journal.pone.0085863.PubMedPubMedCentralCrossRef

38.

Fakhoury M. Role of immunity and inflammation in the pathophysiology of neurodegenerative diseases. Neuro Degener Dis. 2015;15(2):63–9. https://doi.org/10.1159/000369933.CrossRef

39.

Quarantelli M, Giardino G, Prinster A, Aloj G, Carotenuto B, Cirillo E, et al. Steroid treatment in ataxia–telangiectasia induces alterations of functional magnetic resonance imaging during prono-supination task. Eur j Paediatr Neurol. 2013;17(2):135–40. https://doi.org/10.1016/j.ejpn.2012.06.002.PubMedCrossRef

40.

Broccoletti T, Del Giudice E, Cirillo E, Vigliano I, Giardino G, Ginocchio VM, et al. Efficacy of very-low-dose betamethasone on neurological symptoms in ataxia–telangiectasia. Eur J Neurol. 2011;18(4):564–70. https://doi.org/10.1111/j.1468-1331.2010.03203.x.PubMedCrossRef

41.

Broccoletti T, Del Giudice E, Amorosi S, Russo I, Di Bonito M, Imperati F, et al. Steroid-induced improvement of neurological signs in ataxia–telangiectasia patients. Eur J Neurol. 2008;15(3):223–8. https://doi.org/10.1111/j.1468-1331.2008.02060.x.PubMedCrossRef

42.

Buoni S, Zannolli R, Sorrentino L, Fois A. Betamethasone and improvement of neurological symptoms in ataxia–telangiectasia. Arch Neurol. 2006;63(10):1479–82. https://doi.org/10.1001/archneur.63.10.1479.PubMedCrossRef

43.

Zannolli R, Buoni S, Betti G, Salvucci S, Plebani A, Soresina A, et al. A randomized trial of oral betamethasone to reduce ataxia symptoms in ataxia telangiectasia. Mov Disord. 2012;27(10):1312–6. https://doi.org/10.1002/mds.25126.PubMedCrossRef

44.

Rossi L, Castro M, D’Orio F, Damonte G, Serafini S, Bigi L, et al. Low doses of dexamethasone constantly delivered by autologous erythrocytes slow the progression of lung disease in cystic fibrosis patients. Blood Cells Mol Dis. 2004;33(1):57–63. https://doi.org/10.1016/j.bcmd.2004.04.004.PubMedCrossRef

45.

Chessa L, Leuzzi V, Plebani A, Soresina A, Micheli R, D’Agnano D, et al. Intra-erythrocyte infusion of dexamethasone reduces neurological symptoms in ataxia teleangiectasia patients: results of a phase 2 trial. Orphanet J Rare Dis. 2014;9:5. https://doi.org/10.1186/1750-1172-9-5.PubMedPubMedCentralCrossRef

46.

Leuzzi V, Micheli R, D’Agnano D, Molinaro A, Venturi T, Plebani A, et al. Positive effect of erythrocyte-delivered dexamethasone in ataxia–telangiectasia. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e98. https://doi.org/10.1212/NXI.0000000000000098.PubMedPubMedCentralCrossRef

47.

Menotta M, Biagiotti S, Bianchi M, Chessa L, Magnani M. Dexamethasone partially rescues ataxia telangiectasia-mutated (ATM) deficiency in ataxia telangiectasia by promoting a shortened protein variant retaining kinase activity. J Biol Chem. 2012;287(49):41352–63. https://doi.org/10.1074/jbc.M112.344473.PubMedPubMedCentralCrossRef

48.

Mavrou A, Tsangaris GT, Roma E, Kolialexi A. The ATM gene and ataxia telangiectasia. Anticancer Res. 2008;28(1B):401–5.PubMed

49.

Lavin MF. Ataxia–telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol. 2008;9(10):759–69. https://doi.org/10.1038/nrm2514.PubMedCrossRef

50.

van Os NJ, Roeleveld N, Weemaes CM, Jongmans MC, Janssens GO, Taylor AM, et al. Health risks for ataxia–telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline. Clin Genet. 2016;90(2):105–17. https://doi.org/10.1111/cge.12710.PubMedCrossRef

51.

Spring K, Ahangari F, Scott SP, Waring P, Purdie DM, Chen PC, et al. Mice heterozygous for mutation in Atm, the gene involved in ataxia–telangiectasia, have heightened susceptibility to cancer. Nat Genet. 2002;32(1):185–90. https://doi.org/10.1038/ng958.PubMedCrossRef

52.

Mercer JR, Cheng KK, Figg N, Gorenne I, Mahmoudi M, Griffin J, et al. DNA damage links mitochondrial dysfunction to atherosclerosis and the metabolic syndrome. Circ Res. 2010;107(8):1021–31. https://doi.org/10.1161/CIRCRESAHA.110.218966.PubMedPubMedCentralCrossRef

53.

Barlow C, Eckhaus MA, Schaffer AA, Wynshaw-Boris A. Atm haploinsufficiency results in increased sensitivity to sublethal doses of ionizing radiation in mice. Nat Genet. 1999;21(4):359–60. https://doi.org/10.1038/7684.PubMedCrossRef

54.

Worgul BV, Smilenov L, Brenner DJ, Junk A, Zhou W, Hall EJ. Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts. Proc Natl Acad Sci USA. 2002;99(15):9836–9. https://doi.org/10.1073/pnas.162349699.PubMedPubMedCentralCrossRef

55.

Connolly L, Lasarev M, Jordan R, Schwartz JL, Turker MS. Atm haploinsufficiency does not affect ionizing radiation mutagenesis in solid mouse tissues. Radiat Res. 2006;166(1 Pt 1):39–46. https://doi.org/10.1667/RR3578.1.PubMedCrossRef

56.

Mao JH, Wu D, DelRosario R, Castellanos A, Balmain A, Perez-Losada J. Atm heterozygosity does not increase tumor susceptibility to ionizing radiation alone or in a p53 heterozygous background. Oncogene. 2008;27(51):6596–600. https://doi.org/10.1038/onc.2008.280.PubMedCrossRef

57.

Barnes PJ. Mechanisms of development of multimorbidity in the elderly. Eur Respir J. 2015;45(3):790–806. https://doi.org/10.1183/09031936.00229714.PubMedCrossRef

58.

Schneider JG, Finck BN, Ren J, Standley KN, Takagi M, Maclean KH, et al. ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome. Cell Metab. 2006;4(5):377–89. https://doi.org/10.1016/j.cmet.2006.10.002.PubMedCrossRef

59.

Macaulay VM, Salisbury AJ, Bohula EA, Playford MP, Smorodinsky NI, Shiloh Y. Downregulation of the type 1 insulin-like growth factor receptor in mouse melanoma cells is associated with enhanced radiosensitivity and impaired activation of Atm kinase. Oncogene. 2001;20(30):4029–40. https://doi.org/10.1038/sj.onc.1204565.PubMedCrossRef

60.

Ching JK, Luebbert SH, Collins RLt, Zhang Z, Marupudi N, Banerjee S, et al. Ataxia telangiectasia mutated impacts insulin-like growth factor 1 signalling in skeletal muscle. Exp Physiol. 2013;98(2):526–35. https://doi.org/10.1113/expphysiol.2012.066357.PubMedCrossRef

61.

Smirnov DA, Cheung VG. ATM gene mutations result in both recessive and dominant expression phenotypes of genes and microRNAs. Am J Hum Genet. 2008;83(2):243–53. https://doi.org/10.1016/j.ajhg.2008.07.003.PubMedPubMedCentralCrossRef

62.

Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010;49(11):1603–16. https://doi.org/10.1016/j.freeradbiomed.2010.09.006.PubMedPubMedCentralCrossRef

63.

Mittler RROS are good. Trends Plant Sci. 2017;22(1):11–9. https://doi.org/10.1016/j.tplants.2016.08.002.PubMedCrossRef

64.

Kamsler A, Daily D, Hochman A, Stern N, Shiloh Y, Rotman G, et al. Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of brains from Atm-deficient mice. Cancer Res. 2001;61(5):1849–54.PubMed

65.

Barlow C, Dennery PA, Shigenaga MK, Smith MA, Morrow JD, Roberts LJ 2nd, et al. Loss of the ataxia–telangiectasia gene product causes oxidative damage in target organs. Proc Natl Acad Sci USA. 1999;96(17):9915–9.PubMedPubMedCentralCrossRef

66.

Campbell A, Krupp B, Bushman J, Noble M, Proschel C, Mayer-Proschel M. A novel mouse model for ataxia-telangiectasia with a N-terminal mutation displays a behavioral defect and a low incidence of lymphoma but no increased oxidative burden. Hum Mol Genet. 2015;24(22):6331–49. https://doi.org/10.1093/hmg/ddv342.PubMedPubMedCentralCrossRef

67.

Reliene R, Schiestl RH. Experimental antioxidant therapy in ataxia telangiectasia. Clin Med Oncol. 2008;2:431–6.PubMedPubMedCentral

68.

Reliene R, Schiestl RH. Antioxidants suppress lymphoma and increase longevity in Atm-deficient mice. J Nutr. 2007;137(1 Suppl):229S–32S.PubMedCrossRef

69.

D’Souza AD, Parish IA, Krause DS, Kaech SM, Shadel GS. Reducing mitochondrial ROS improves disease-related pathology in a mouse model of ataxia–telangiectasia. Mol Therapy. 2013;21(1):42–8. https://doi.org/10.1038/mt.2012.203.CrossRef

70.

Kim J, Wong PK. Oxidative stress is linked to ERK1/2-p16 signaling-mediated growth defect in ATM-deficient astrocytes. J Biol Chem. 2009;284(21):14396–404. https://doi.org/10.1074/jbc.M808116200.PubMedPubMedCentralCrossRef

71.

Guo Z, Kozlov S, Lavin MF, Person MD, Paull TT. ATM activation by oxidative stress. Science. 2010;330(6003):517–21. https://doi.org/10.1126/science.1192912.PubMedCrossRef

72.

Yeo AJ, Fantino E, Czovek D, Wainwright CE, Sly PD, Lavin MF. Loss of ATM in airway epithelial cells is associated with susceptibility to oxidative stress. Am J Respir Crit Care Med. 2017;196(3):391–3. https://doi.org/10.1164/rccm.201611-2210LE.PubMedCrossRef

73.

Pallardo FV, Lloret A, Lebel M, d’Ischia M, Cogger VC, Le Couteur DG, et al. Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia–Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome. Biogerontology. 2010;11(4):401–19. https://doi.org/10.1007/s10522-010-9269-4.PubMedCrossRef

74.

Ambrose M, Goldstine JV, Gatti RA. Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells. Hum Mol Genet. 2007;16(18):2154–64. https://doi.org/10.1093/hmg/ddm166.PubMedCrossRef

75.

Maciejczyk M, Mikoluc B, Pietrucha B, Heropolitanska-Pliszka E, Pac M, Motkowski R, et al. Oxidative stress, mitochondrial abnormalities and antioxidant defense in ataxia–telangiectasia, Bloom syndrome and Nijmegen breakage syndrome. Redox Biol. 2016;11:375–83. https://doi.org/10.1016/j.redox.2016.12.030.PubMedPubMedCentralCrossRef

76.

Tripathi DN, Zhang J, Jing J, Dere R, Walker CL. A new role for ATM in selective autophagy of peroxisomes (pexophagy). Autophagy. 2016;12(4):711–2. https://doi.org/10.1080/15548627.2015.1123375.PubMedPubMedCentralCrossRef

77.

Zhang J, Tripathi DN, Jing J, Alexander A, Kim J, Powell RT, et al. ATM functions at the peroxisome to induce pexophagy in response to ROS. Nat Cell Biol. 2015;17(10):1259–69. https://doi.org/10.1038/ncb3230.PubMedPubMedCentralCrossRef

78.

Le Guezennec X, Brichkina A, Huang YF, Kostromina E, Han W, Bulavin DV. Wip1-dependent regulation of autophagy, obesity, and atherosclerosis. Cell Metab. 2012;16(1):68–80. https://doi.org/10.1016/j.cmet.2012.06.003.PubMedCrossRef

79.

Yan Y, Finkel T. Autophagy as a regulator of cardiovascular redox homeostasis. Free Radic Biol Med. 2016. https://doi.org/10.1016/j.freeradbiomed.2016.12.003.CrossRefPubMedPubMedCentral

80.

Shiloh Y, Tabor E, Becker Y. Abnormal response of ataxia–telangiectasia cells to agents that break the deoxyribose moiety of DNA via a targeted free radical mechanism. Carcinogenesis. 1983;4(10):1317–22.PubMedCrossRef

81.

Yi M, Rosin MP, Anderson CK. Response of fibroblast cultures from ataxia–telangiectasia patients to oxidative stress. Cancer Lett. 1990;54(1–2):43–50.PubMedCrossRef

82.

Sharma NK, Lebedeva M, Thomas T, Kovalenko OA, Stumpf JD, Shadel GS, et al. Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia. DNA Repair. 2014;13:22–31. https://doi.org/10.1016/j.dnarep.2013.11.002.PubMedCrossRef

83.

Stratigi K, Chatzidoukaki O, Garinis GA. DNA damage-induced inflammation and nuclear architecture. Mech Ageing Dev. 2016. https://doi.org/10.1016/j.mad.2016.09.008.PubMedCrossRef

84.

Radoshevich L, Dussurget O. Cytosolic innate immune sensing and signaling upon infection. Front Microbiol. 2016;7:313. https://doi.org/10.3389/fmicb.2016.00313.PubMedPubMedCentralCrossRef

85.

Nakad R, Schumacher B. DNA damage response and immune defense: links and mechanisms. Front Genet. 2016;7:147. https://doi.org/10.3389/fgene.2016.00147.PubMedPubMedCentralCrossRef

86.

Paludan SR, Bowie AG. Immune sensing of DNA. Immunity. 2013;38(5):870–80. https://doi.org/10.1016/j.immuni.2013.05.004.PubMedPubMedCentralCrossRef

87.

Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009;458(7237):514–8. https://doi.org/10.1038/nature07725.PubMedPubMedCentralCrossRef

88.

Choubey D, Panchanathan R. IFI16, an amplifier of DNA-damage response: Role in cellular senescence and aging-associated inflammatory diseases. Ageing Res Rev. 2016;28:27–36. https://doi.org/10.1016/j.arr.2016.04.002.PubMedCrossRef

89.

Mankan AK, Hornung V. Sox2 as a servant of two masters. Nat Immunol. 2015;16(4):335–6. https://doi.org/10.1038/ni.3121.PubMedCrossRef

90.

Karakasilioti I, Kamileri I, Chatzinikolaou G, Kosteas T, Vergadi E, Robinson AR, et al. DNA damage triggers a chronic autoinflammatory response, leading to fat depletion in NER progeria. Cell Metab. 2013;18(3):403–15. https://doi.org/10.1016/j.cmet.2013.08.011.PubMedPubMedCentralCrossRef

91.

Yu E, Calvert PA, Mercer JR, Harrison J, Baker L, Figg NL, et al. Mitochondrial DNA damage can promote atherosclerosis independently of reactive oxygen species through effects on smooth muscle cells and monocytes and correlates with higher-risk plaques in humans. Circulation. 2013;128(7):702–12. https://doi.org/10.1161/CIRCULATIONAHA.113.002271.PubMedCrossRef

92.

Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12(3):222–30. https://doi.org/10.1038/ni.1980.PubMedCrossRef

93.

van der Burgh R, Nijhuis L, Pervolaraki K, Compeer EB, Jongeneel LH, van Gijn M, et al. Defects in mitochondrial clearance predispose human monocytes to interleukin-1beta hypersecretion. J Biol Chem. 2014;289(8):5000–12. https://doi.org/10.1074/jbc.M113.536920.PubMedCrossRef

94.

Martinon F. Dangerous liaisons: mitochondrial DNA meets the NLRP3 inflammasome. Immunity. 2012;36(3):313–5. https://doi.org/10.1016/j.immuni.2012.03.005.PubMedCrossRef

95.

Palmai-Pallag T, Bachrati CZ. Inflammation-induced DNA damage and damage-induced inflammation: a vicious cycle. Microbes Infect. 2014;16(10):822–32. https://doi.org/10.1016/j.micinf.2014.10.001.PubMedCrossRef

96.

Pateras IS, Havaki S, Nikitopoulou X, Vougas K, Townsend PA, Panayiotidis MI, et al. The DNA damage response and immune signaling alliance: Is it good or bad? Nature decides when and where. Pharmacol Therap. 2015;154:36–56. https://doi.org/10.1016/j.pharmthera.2015.06.011.CrossRef

97.

Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965;37:614–36.PubMedCrossRef

98.

Shimizu I, Yoshida Y, Suda M, Minamino T. DNA damage response and metabolic disease. Cell Metab. 2014;20(6):967–77. https://doi.org/10.1016/j.cmet.2014.10.008.PubMedCrossRef

99.

Jackson JG, Pereira-Smith OM. p53 is preferentially recruited to the promoters of growth arrest genes p21 and GADD45 during replicative senescence of normal human fibroblasts. Cancer Res. 2006;66(17):8356–60. https://doi.org/10.1158/0008-5472.CAN-06-1752.PubMedCrossRef

100.

Cao X, Li M. A new pathway for senescence regulation. Genom Proteom Bioinf. 2015;13(6):333–5.CrossRef

101.

Kang HT, Park JT, Choi K, Kim Y, Choi HJC, Jung CW, et al. Chemical screening identifies ATM as a target for alleviating senescence. Nat Chem Biol. 2017;13(6):616–23. https://doi.org/10.1038/nchembio.2342.PubMedCrossRef

102.

Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K, et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 2005;434(7035):864–70. https://doi.org/10.1038/nature03482.PubMedCrossRef

103.

Wallace MD, Southard TL, Schimenti KJ, Schimenti JC. Role of DNA damage response pathways in preventing carcinogenesis caused by intrinsic replication stress. Oncogene. 2014;33(28):3688–95. https://doi.org/10.1038/onc.2013.339.PubMedCrossRef

104.

Wunderlich R, Ruehle PF, Deloch L, Unger K, Hess J, Zitzelsberger H, et al. Interconnection between DNA damage, senescence, inflammation, and cancer. Front Biosci. 2017;22:348–69.CrossRef

105.

Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008;133(6):1019–31. https://doi.org/10.1016/j.cell.2008.03.039.PubMedCrossRef

106.

Acosta JC, O’Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell. 2008;133(6):1006–18. https://doi.org/10.1016/j.cell.2008.03.038.PubMedCrossRef

107.

Liu D, Hornsby PJ. Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res. 2007;67(7):3117–26. https://doi.org/10.1158/0008-5472.CAN-06-3452.PubMedCrossRef

108.

Hui CW, Herrup K. Individual cytokines modulate the neurological symptoms of ATM deficiency in a region specific Manner(1,2,3). eNeuro. 2015. https://doi.org/10.1523/ENEURO.0032-15.2015.PubMedPubMedCentralCrossRef

109.

Soriani A, Zingoni A, Cerboni C, Iannitto ML, Ricciardi MR, Di Gialleonardo V, et al. ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood. 2009;113(15):3503–11. https://doi.org/10.1182/blood-2008-08-173914.PubMedCrossRef

110.

Miyamoto S. Nuclear initiated NF-kappaB signaling: NEMO and ATM take center stage. Cell Res. 2011;21(1):116–30. https://doi.org/10.1038/cr.2010.179.PubMedCrossRef

111.

Gasser S, Orsulic S, Brown EJ, Raulet DH. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature. 2005;436(7054):1186–90. https://doi.org/10.1038/nature03884.PubMedPubMedCentralCrossRef

112.

Weil S, Memmer S, Lechner A, Huppert V, Giannattasio A, Becker T, et al. Natural Killer group 2D ligand depletion reconstitutes natural killer cell immunosurveillance of head and neck squamous cell carcinoma. Front Immunol. 2017;8:387. https://doi.org/10.3389/fimmu.2017.00387.PubMedPubMedCentralCrossRef

113.

Wiemann K, Mittrucker HW, Feger U, Welte SA, Yokoyama WM, Spies T, et al. Systemic NKG2D down-regulation impairs NK and CD8 T cell responses in vivo. J Immunol. 2005;175(2):720–9.PubMedCrossRef

114.

Molfetta R, Quatrini L, Zitti B, Capuano C, Galandrini R, Santoni A, et al. Regulation of NKG2D expression and signaling by endocytosis. Trends Immunol. 2016;37(11):790–802. https://doi.org/10.1016/j.it.2016.08.015.PubMedCrossRef

115.

Exley AR, Buckenham S, Hodges E, Hallam R, Byrd P, Last J, et al. Premature ageing of the immune system underlies immunodeficiency in ataxia telangiectasia. Clin Immunol. 2011;140(1):26–36. https://doi.org/10.1016/j.clim.2011.03.007.PubMedCrossRef

116.

Gatei M, Shkedy D, Khanna KK, Uziel T, Shiloh Y, Pandita TK, et al. Ataxia–telangiectasia: chronic activation of damage-responsive functions is reduced by alpha-lipoic acid. Oncogene. 2001;20(3):289–94. https://doi.org/10.1038/sj.onc.1204111.PubMedCrossRef

117.

Rashi-Elkeles S, Elkon R, Weizman N, Linhart C, Amariglio N, Sternberg G, et al. Parallel induction of ATM-dependent pro- and antiapoptotic signals in response to ionizing radiation in murine lymphoid tissue. Oncogene. 2006;25(10):1584–92. https://doi.org/10.1038/sj.onc.1209189.PubMedCrossRef

118.

Stern N, Hochman A, Zemach N, Weizman N, Hammel I, Shiloh Y, et al. Accumulation of DNA damage and reduced levels of nicotine adenine dinucleotide in the brains of Atm-deficient mice. J Biol Chem. 2002;277(1):602–8. https://doi.org/10.1074/jbc.M106798200.PubMedCrossRef

119.

Shiloh Y, Lederman HM. Ataxia–telangiectasia (A–T): an emerging dimension of premature ageing. Ageing Res Rev. 2017;33:76–88. https://doi.org/10.1016/j.arr.2016.05.002.PubMedCrossRef

120.

Lasry A, Ben-Neriah Y. Senescence-associated inflammatory responses: aging and cancer perspectives. Trends Immunol. 2015;36(4):217–28. https://doi.org/10.1016/j.it.2015.02.009.PubMedCrossRef

121.

Metcalfe JA, Parkhill J, Campbell L, Stacey M, Biggs P, Byrd PJ, et al. Accelerated telomere shortening in ataxia telangiectasia. Nat Genet. 1996;13(3):350–3.PubMedCrossRef

122.

Smilenov LB, Morgan SE, Mellado W, Sawant SG, Kastan MB, Pandita TK. Influence of ATM function on telomere metabolism. Oncogene. 1997;15(22):2659–65. https://doi.org/10.1038/sj.onc.1201449.PubMedCrossRef

123.

Xia SJ, Shammas MA, Shmookler Reis RJ. Reduced telomere length in ataxia–telangiectasia fibroblasts. Mutat Res. 1996;364(1):1–11.PubMedCrossRef

124.

Naka K, Tachibana A, Ikeda K, Motoyama N. Stress-induced premature senescence in hTERT-expressing ataxia telangiectasia fibroblasts. J Biol Chem. 2004;279(3):2030–7. https://doi.org/10.1074/jbc.M309457200.PubMedCrossRef

125.

Wood LD, Halvorsen TL, Dhar S, Baur JA, Pandita RK, Wright WE, et al. Characterization of ataxia telangiectasia fibroblasts with extended life-span through telomerase expression. Oncogene. 2001;20(3):278–88. https://doi.org/10.1038/sj.onc.1204072.PubMedCrossRef

126.

Wong KK, Maser RS, Bachoo RM, Menon J, Carrasco DR, Gu Y, et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature. 2003;421(6923):643–8. https://doi.org/10.1038/nature01385.PubMedCrossRef

127.

Arnoult N, Karlseder J. Complex interactions between the DNA-damage response and mammalian telomeres. Nat Struct Mol Biol. 2015;22(11):859–66. https://doi.org/10.1038/nsmb.3092.PubMedPubMedCentralCrossRef

128.

Chen H, Ruiz PD, McKimpson WM, Novikov L, Kitsis RN, Gamble MJ. MacroH2A1 and ATM play opposing roles in paracrine senescence and the senescence-associated secretory phenotype. Mol Cell. 2015;59(5):719–31. https://doi.org/10.1016/j.molcel.2015.07.011.PubMedPubMedCentralCrossRef

129.

Kang C, Xu QK, Martin TD, Li MZ, Demaria M, Aron L, et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science. 2015;349(6255):1503-+. https://doi.org/10.1126/science.aaa5612.CrossRef

130.

Aird KM, Worth AJ, Snyder NW, Lee JV, Sivanand S, Liu Q, et al. ATM couples replication stress and metabolic reprogramming during cellular senescence. Cell Rep. 2015;11(6):893–901. https://doi.org/10.1016/j.celrep.2015.04.014.PubMedPubMedCentralCrossRef

131.

Cosentino C, Grieco D, Costanzo V. ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair. EMBO J. 2011;30(3):546–55. https://doi.org/10.1038/emboj.2010.330.PubMedCrossRef

132.

Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006;12(4):446–51. https://doi.org/10.1038/nm1388.PubMedCrossRef

133.

Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature. 2004;431(7011):997–1002. https://doi.org/10.1038/nature02989.PubMedCrossRef

134.

Liang R, Ghaffari S. Stem cells, redox signaling, and stem cell aging. Antioxid Redox Signal. 2014;20(12):1902–16. https://doi.org/10.1089/ars.2013.5300.PubMedPubMedCentralCrossRef

135.

Sato A, Okada M, Shibuya K, Watanabe E, Seino S, Narita Y, et al. Pivotal role for ROS activation of p38 MAPK in the control of differentiation and tumor-initiating capacity of glioma-initiating cells. Stem Cell Res. 2014;12(1):119–31. https://doi.org/10.1016/j.scr.2013.09.012.PubMedCrossRef

136.

Bhattacharya R, Mustafi SB, Street M, Dey A, Dwivedi SK. Bmi-1: at the crossroads of physiological and pathological biology. Genes Dis. 2015;2(3):225–39. https://doi.org/10.1016/j.gendis.2015.04.001.PubMedPubMedCentralCrossRef

137.

Li J, Herrup K. Alterations in epigenetic systems in AT neurodegeneration. Biohelikon Cell Biol. 2013;1:1–2.CrossRef

138.

Consalvi S, Brancaccio A, Dall’Agnese A, Puri PL, Palacios D. Praja1 E3 ubiquitin ligase promotes skeletal myogenesis through degradation of EZH2 upon p38alpha activation. Nat Commun. 2017;8:13956. https://doi.org/10.1038/ncomms13956.PubMedPubMedCentralCrossRef

139.

Feng X, Juan AH, Wang HA, Ko KD, Zare H, Sartorelli V. Polycomb Ezh2 controls the fate of GABAergic neurons in the embryonic cerebellum. Development. 2016;143(11):1971–80. https://doi.org/10.1242/dev.132902.PubMedPubMedCentralCrossRef

140.

Kim J, Wong PK. Loss of ATM impairs proliferation of neural stem cells through oxidative stress-mediated p38 MAPK signaling. Stem Cells. 2009;27(8):1987–98. https://doi.org/10.1002/stem.125.PubMedCrossRef

141.

Kim J, Hwangbo J, Wong PK. p38 MAPK-Mediated Bmi-1 down-regulation and defective proliferation in ATM-deficient neural stem cells can be restored by Akt activation. PLoS One. 2011;6(1):e16615. https://doi.org/10.1371/journal.pone.0016615.PubMedPubMedCentralCrossRef

142.

Harbort CJ, Soeiro-Pereira PV, von Bernuth H, Kaindl AM, Costa-Carvalho BT, Condino-Neto A, et al. Neutrophil oxidative burst activates ATM to regulate cytokine production and apoptosis. Blood. 2015;126(26):2842–51. https://doi.org/10.1182/blood-2015-05-645424.PubMedPubMedCentralCrossRef

143.

Kondo T, Kobayashi J, Saitoh T, Maruyama K, Ishii KJ, Barber GN, et al. DNA damage sensor MRE11 recognizes cytosolic double-stranded DNA and induces type I interferon by regulating STING trafficking. Proc Natl Acad Sci USA. 2013;110(8):2969–74. https://doi.org/10.1073/pnas.1222694110.PubMedPubMedCentralCrossRef

144.

Ahn J, Xia T, Konno H, Konno K, Ruiz P, Barber GN. Inflammation-driven carcinogenesis is mediated through STING. Nat Commun. 2014;5:5166. https://doi.org/10.1038/ncomms6166.PubMedPubMedCentralCrossRef

145.

Yu Q, Katlinskaya YV, Carbone CJ, Zhao B, Katlinski KV, Zheng H, et al. DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function. Cell Rep. 2015;11(5):785–97. https://doi.org/10.1016/j.celrep.2015.03.069.PubMedPubMedCentralCrossRef

146.

Petersen AJ, Katzenberger RJ, Wassarman DA. The innate immune response transcription factor relish is necessary for neurodegeneration in a Drosophila model of ataxia–telangiectasia. Genetics. 2013;194(1):133–42. https://doi.org/10.1534/genetics.113.150854.PubMedPubMedCentralCrossRef

147.

Quek H, Luff J, Cheung K, Kozlov S, Gatei M, Lee CS, et al. A rat model of ataxia–telangiectasia: evidence for a neurodegenerative phenotype. Hum Mol Genet. 2016. https://doi.org/10.1093/hmg/ddw371.CrossRef

148.

Pereira-Lopes S, Tur J, Calatayud-Subias JA, Lloberas J, Stracker TH, Celada A. NBS1 is required for macrophage homeostasis and functional activity in mice. Blood. 2015;126(22):2502–10. https://doi.org/10.1182/blood-2015-04-637371.PubMedCrossRef

149.

Bednarski JJ. DNA damage signals inhibit neutrophil function. Blood. 2015;126(26):2773–4. https://doi.org/10.1182/blood-2015-11-678672.PubMedPubMedCentralCrossRef

150.

Herrtwich L, Nanda I, Evangelou K, Nikolova T, Horn V, Sagar, et al. DNA damage signaling instructs polyploid macrophage fate in granulomas. Cell. 2016;167(5):1264-80 e18. https://doi.org/10.1016/j.cell.2016.09.054.CrossRef

151.

Wang Q, Franks HA, Lax SJ, El Refaee M, Malecka A, Shah S, et al. The ataxia telangiectasia mutated kinase pathway regulates IL-23 expression by human dendritic cells. J Immunol. 2013;190(7):3246–55. https://doi.org/10.4049/jimmunol.1201484.PubMedPubMedCentralCrossRef

152.

Li S, Zhang L, Chen T, Tian B, Deng X, Zhao Z, et al. Functional polymorphism rs189037 in the promoter region of ATM gene is associated with angiographically characterized coronary stenosis. Atherosclerosis. 2011;219(2):694–7. https://doi.org/10.1016/j.atherosclerosis.2011.08.040.PubMedCrossRef

153.

Su Y, Swift M. Mortality rates among carriers of ataxia–telangiectasia mutant alleles. Ann Intern Med. 2000;133(10):770–8.PubMedCrossRef

154.

Figueiredo N, Chora A, Raquel H, Pejanovic N, Pereira P, Hartleben B, et al. Anthracyclines induce DNA damage response-mediated protection against severe sepsis. Immunity. 2013;39(5):874–84. https://doi.org/10.1016/j.immuni.2013.08.039.PubMedPubMedCentralCrossRef

155.

Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009;11(8):973–9. https://doi.org/10.1038/ncb1909.PubMedPubMedCentralCrossRef

156.

Chen WT, Ebelt ND, Stracker TH, Xhemalce B, Van Den Berg CL, Miller KM. ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion. eLife. 2015. https://doi.org/10.7554/eLife.07270.CrossRefPubMedPubMedCentral

157.

Quick KL, Dugan LL. Superoxide stress identifies neurons at risk in a model of ataxia–telangiectasia. Ann Neurol. 2001;49(5):627–35.PubMedCrossRef

Titel: Inflammation, a significant player of Ataxia–Telangiectasia pathogenesis?
verfasst von: Majid Zaki-Dizaji
Seyed Mohammad Akrami
Gholamreza Azizi
Hassan Abolhassani
Asghar Aghamohammadi
Publikationsdatum: 26.03.2018
Verlag: Springer International Publishing
Erschienen in: Inflammation Research / Ausgabe 7/2018
Print ISSN: 1023-3830
Elektronische ISSN: 1420-908X
DOI: https://doi.org/10.1007/s00011-018-1142-y

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