The immunoproteasome-specific inhibitor ONX 0914 reverses susceptibility to acute viral myocarditis

EMBO Molecular Medicine

Volumn 10, Issue 2, 2018, Pages 200-218

  Althof, Nadine ^a,b   Goetzke, Carl Christoph ^a   Kespohl, Meike ^a,b   Voss, Karolin ^a   Heuser, Arnd ^b   Pinkert, Sandra ^a   Kaya, Ziya ^c,d   Klingel, Karin ^e   Beling, Antje ^a,b  

^a BERLIN INSTITUTE OF HEALTH   (Germany)

^b MAX DELBRÜCK CENTER FOR MOLECULAR MEDICINE   (Germany)

^c UNIVERSITY HOSPITAL HEIDELBERG   (Germany)

^d DZHK GERMAN CENTRE FOR CARDIOVASCULAR RESEARCH   (Germany)

^e UNIVERSITY HOSPITAL TÜBINGEN   (Germany)

Author keywords

immunology and inflammation; infectious diseases; myocarditis; proteasome; virus

Indexed keywords

ONX 0914; PR 957; PROTEASOME INHIBITOR; UNCLASSIFIED DRUG; OLIGOPEPTIDE; PR-957;

ADAPTIVE IMMUNITY; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL INFILTRATION; CELL LOSS; CHEMOKINESIS; CONTROLLED STUDY; CYTOKINE PRODUCTION; DISEASE COURSE; DRUG EFFECT; HEART OUTPUT; HOMEOSTASIS; HUMAN; HUMAN CELL; INFECTION SENSITIVITY; MACROPHAGE; MALE; MONOCYTE; MORTALITY; MOUSE; NONHUMAN; PRIORITY JOURNAL; SEPSIS; VIRUS LOAD; VIRUS MYOCARDITIS; ANIMAL; CELL CULTURE; COXSACKIE VIRUS INFECTION; ENTEROVIRUS; IMMUNOLOGICAL MEMORY; IMMUNOLOGY; MYOCARDITIS; VIROLOGY;

ANIMALS; CARDIAC OUTPUT; CELLS, CULTURED; COXSACKIEVIRUS INFECTIONS; ENTEROVIRUS; IMMUNOLOGIC MEMORY; MICE; MODELS, ANIMAL; MYOCARDITIS; OLIGOPEPTIDES; PROTEASOME INHIBITORS;

EID: 85039799494     PISSN: 17574676     EISSN: 17574684     Source Type: Journal    
DOI: 10.15252/emmm.201708089     Document Type: Article

References (61)

1. Althof N, Harkins S, Kemball CC, Flynn CT, Alirezaei M, Whitton JL (2014) In vivo ablation of type I interferon receptor from cardiomyocytes delays coxsackieviral clearance and accelerates myocardial disease. J Virol 88: 5087–5099
2. Basler M, Dajee M, Moll C, Groettrup M, Kirk CJ (2010) Prevention of experimental colitis by a selective inhibitor of the immunoproteasome. J Immunol 185: 634–641
3. Basler M, Beck U, Kirk CJ, Groettrup M (2011) The antiviral immune response in mice devoid of immunoproteasome activity. J Immunol 187: 5548–5557
4. Basler M, Kirk CJ, Groettrup M (2013) The immunoproteasome in antigen processing and other immunological functions. Curr Opin Immunol 25: 74–80
5. Basler M, Mundt S, Muchamuel T, Moll C, Jiang J, Groettrup M, Kirk CJ (2014) Inhibition of the immunoproteasome ameliorates experimental autoimmune encephalomyelitis. EMBO Mol Med 6: 226–238
6. Bitzer A, Basler M, Krappmann D, Groettrup M (2017) Immunoproteasome subunit deficiency has no influence on the canonical pathway of NF-kappaB activation. Mol Immunol 83: 147–153
7. Blasius AL, Beutler B (2010) Intracellular toll-like receptors. Immunity 32: 305–315
8. Brinkmann V, Laube B, Abu Abed U, Goosmann C, Zychlinsky A (2010) Neutrophil extracellular traps: how to generate and visualize them. J Vis Exp 36: 1724
9. Cain BS, Meldrum DR, Dinarello CA, Meng X, Joo KS, Banerjee A, Harken AH (1999) Tumor necrosis factor-alpha and interleukin-1beta synergistically depress human myocardial function. Critic Care Med 27: 1309–1318
10. Chow LH, Gauntt CJ, McManus BM (1991) Differential effects of myocarditic variants of Coxsackievirus B3 in inbred mice. A pathologic characterization of heart tissue damage. Lab Invest 64: 55–64
11. Cooper LT (2009) Medical progress: myocarditis. N Engl J Med 360: 1526–1538
12. Corsten MF, Schroen B, Heymans S (2012) Inflammation in viral myocarditis: friend or foe? Trends Mol Med 18: 426–437
13. Ebstein F, Voigt A, Lange N, Warnatsch A, Schroter F, Prozorovski T, Kuckelkorn U, Aktas O, Seifert U, Kloetzel PM et al (2013) Immunoproteasomes are important for proteostasis in immune responses. Cell 152: 935–937
14. Epelman S, Liu PP, Mann DL (2015) Role of innate and adaptive immune mechanisms in cardiac injury and repair. Nat Rev Immunol 15: 117–129
15. + T cell responses to the human protozoan parasite Trypanosoma cruzi. PLoS Pathog 12: e1005593
16. Fehling HJ, Swat W, Laplace C, Kuhn R, Rajewsky K, Muller U, Vonboehmer H (1994) Mhc class-I expression in mice lacking the proteasome subunit Lmp-7. Science 265: 1234–1237
17. Ginhoux F, Jung S (2014) Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 14: 392–404
18. Groettrup M, Kirk CJ, Basler M (2010) Proteasomes in immune cells: more than peptide producers? Nat Rev Immunol 10: 73–78
19. Hensley SE, Zanker D, Dolan BP, David A, Hickman HD, Embry AC, Skon CN, Grebe KM, Griffin TA, Chen WS et al (2010) Unexpected role for the immunoproteasome subunit LMP2 in antiviral humoral and innate immune responses. J Immunol 184: 4115–4122
20. Hiraoka Y, Kishimoto C, Takada H, Suzaki N, Shiraki K (1995) Colony-stimulating factors and coxackievirus B3 myocarditis in mice: macrophage colony-stimulating factor suppresses acute myocarditis with increasing interferon-alpha. Am Heart J 130: 1259–1264
21. Hirasawa K, Tsutsui S, Takeda M, Mizutani M, Itagaki S, Doi K (1996) Depletion of Mac1-positive macrophages protects DBA/2 mice from encephalomyocarditis virus-induced myocarditis and diabetes. J Gen Virol 77(Pt. 4): 737–741
22. Huber EM, Basler M, Schwab R, Heinemeyer W, Kirk CJ, Groettrup M, Groll M (2012) Immuno- and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity. Cell 148: 727–738
23. Ichikawa HT, Conley T, Muchamuel T, Jiang J, Lee S, Owen T, Barnard J, Nevarez S, Goldman BI, Kirk CJ et al (2012) Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells. Arthritis Rheum 64: 493–503
24. Jakel S, Kuckelkorn U, Szalay G, Plotz M, Textoris-Taube K, Opitz E, Klingel K, Stevanovic S, Kandolf R, Kotsch K et al (2009) Differential interferon responses enhance viral epitope generation by myocardial immunoproteasomes in murine enterovirus myocarditis. Am J Pathol 175: 510–518
25. Jaquenod De Giusti C, Ure AE, Rivadeneyra L, Schattner M, Gomez RM (2015) Macrophages and galectin 3 play critical roles in CVB3-induced murine acute myocarditis and chronic fibrosis. J Mol Cell Physiol 85: 58–70
26. Jenne CN, Wong CH, Zemp FJ, McDonald B, Rahman MM, Forsyth PA, McFadden G, Kubes P (2013) Neutrophils recruited to sites of infection protect from virus challenge by releasing neutrophil extracellular traps. Cell Host Microbe 13: 169–180
27. Jenne CN, Kubes P (2015) Virus-induced NETs–critical component of host defense or pathogenic mediator? PLoS Pathog 11: e1004546
28. Kalim KW, Basler M, Kirk CJ, Groettrup M (2012) Immunoproteasome subunit LMP7 deficiency and inhibition suppresses Th1 and Th17 but enhances regulatory T cell differentiation. J Immunol 189: 4182–4193
29. Kincaid EZ, Che JW, York I, Escobar H, Reyes-Vargas E, Delgado JC, Welsh RM, Karow ML, Murphy AJ, Valenzuela DM et al (2012) Mice completely lacking immunoproteasomes show major changes in antigen presentation. Nat Immunol 13: 129–135
30. Kindermann I, Kindermann M, Kandolf R, Klingel K, Bultmann B, Muller T, Lindinger A, Bohm M (2008) Predictors of outcome in patients with suspected myocarditis. Circulation 118: 639–648
31. Klingel K, Hohenadl C, Canu A, Albrecht M, Seemann M, Mall G, Kandolf R (1992) Ongoing enterovirus-induced myocarditis is associated with persistent heart-muscle infection – quantitative-analysis of virus-replication, tissue-damage, and inflammation. Proc Natl Acad Sci USA 89: 314–318
32. Klingel K, Stephan S, Sauter M, Zell R, McManus BM, Bultmann B, Kandolf R (1996) Pathogenesis of murine enterovirus myocarditis: virus dissemination and immune cell targets. J Virol 70: 8888–8895
33. Kumar A, Thota V, Dee L, Olson J, Uretz E, Parrillo JE (1996) Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum. J Exp Med 183: 949–958
34. Leuschner F, Courties G, Dutta P, Mortensen LJ, Gorbatov R, Sena B, Novobrantseva TI, Borodovsky A, Fitzgerald K, Koteliansky V et al (2015) Silencing of CCR2 in myocarditis. Eur Heart J 36: 1478–1488
35. Luo H, Yanagawa B, Zhang J, Luo Z, Zhang M, Esfandiarei M, Carthy C, Wilson JE, Yang D, McManus BM (2002) Coxsackievirus B3 replication is reduced by inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway. J Virol 76: 3365–3373
36. Mann DL (2011) The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls. Circ Res 108: 1133–1145
37. Mena I, Perry CM, Harkins S, Rodriguez F, Gebhard J, Whitton JL (1999) The role of B lymphocytes in coxsackievirus B3 infection. Am J Pathol 155: 1205–1215
38. Mishto M, Liepe J, Textoris-Taube K, Keller C, Henklein P, Weberruss M, Dahlmann B, Enenkel C, Voigt A, Kuckelkorn U et al (2014) Proteasome isoforms exhibit only quantitative differences in cleavage and epitope generation. Eur J Immunol 44: 3508–3521
39. Moebius J, van den Broek M, Groettrup M, Basler M (2010) Immunoproteasomes are essential for survival and expansion of T cells in virus-infected mice. Eur J Immunol 40: 3439–3449
40. Muchamuel T, Basler M, Aujay MA, Suzuki E, Kalim KW, Lauer C, Sylvain C, Ring ER, Shields J, Jiang J et al (2009) A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat Med 15: 781–787
41. Mundt S, Basler M, Buerger S, Engler H, Groettrup M (2016a) Inhibiting the immunoproteasome exacerbates the pathogenesis of systemic Candida albicans infection in mice. Sci Rep 6: 19434
42. Mundt S, Engelhardt B, Kirk CJ, Groettrup M, Basler M (2016b) Inhibition and deficiency of the immunoproteasome subunit LMP7 attenuates LCMV-induced meningitis. Eur J Immunol 46: 104–113
43. Opavsky MA, Martino T, Rabinovitch M, Penninger J, Richardson C, Petric M, Trinidad C, Butcher L, Chan J, Liu PP (2002) Enhanced ERK-1/2 activation in mice susceptible to coxsackievirus-induced myocarditis. J Clin Invest 109: 1561–1569
44. Opitz E, Koch A, Klingel K, Schmidt F, Prokop S, Rahnefeld A, Sauter M, Heppner FL, Volker U, Kandolf R et al (2011) Impairment of immunoproteasome function by beta5i/LMP7 subunit deficiency results in severe enterovirus myocarditis. PLoS Pathogens 7: 1–13
45. Paeschke A, Possehl A, Klingel K, Voss M, Voss K, Kespohl M, Sauter M, Overkleeft HS, Althof N, Garlanda C et al (2016) The immunoproteasome controls the availability of the cardioprotective pattern recognition molecule Pentraxin3. Eur J Immunol 46: 619–633
46. Rahnefeld A, Ebstein F, Albrecht N, Opitz E, Kuckelkorn U, Stangl K, Rehm A, Kloetzel PM, Voigt A (2011) Antigen-presentation capacity of dendritic cells is impaired in ongoing enterovirus myocarditis. Eur J Immunol 41: 2774–2781
47. Rahnefeld A, Klingel K, Schuermann A, Diny NL, Althof N, Lindner A, Bleienheuft P, Savvatis K, Respondek D, Opitz E et al (2014) Ubiquitin-like protein ISG15 (Interferon-Stimulated Gene of 15 kDa) in host defense against heart failure in a mouse model of virus-induced cardiomyopathy. Circulation 130: 1589–1600
48. Respondek D, Voss M, Kuhlewindt I, Klingel K, Kruger E, Beling A (2017) PA28 modulates antigen processing and viral replication during coxsackievirus B3 infection. PLoS One 12: e0173259
49. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348: 2609–2617
50. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H et al (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352: 2487–2498
51. Ronkina N, Kotlyarov A, Dittrich-Breiholz O, Kracht M, Hitti E, Milarski K, Askew R, Marusic S, Lin LL, Gaestel M et al (2007) The mitogen-activated protein kinase (MAPK)-activated protein kinases MK2 and MK3 cooperate in stimulation of tumor necrosis factor biosynthesis and stabilization of p38 MAPK. Mol Cell Biol 27: 170–181
52. Sagar S, Liu PP, Cooper LT Jr (2012) Myocarditis. Lancet 379: 738–747
53. Saitoh T, Komano J, Saitoh Y, Misawa T, Takahama M, Kozaki T, Uehata T, Iwasaki H, Omori H, Yamaoka S et al (2012) Neutrophil extracellular traps mediate a host defense response to human immunodeficiency virus-1. Cell Host Microbe 12: 109–116
54. Schwarz K, van den Broek M, Kostka S, Kraft R, Soza A, Schmidtke G, Kloetzel PM, Groettrup M (2000) Overexpression of the proteasome subunits LMP2, LMP7, and MECL-1, but not PA28 alpha/beta, enhances the presentation of an immunodominant lymphocytic choriomeningitis virus T cell epitope. J Immunol 165: 768–778
55. Seifert U, Bialy LP, Ebstein F, Bech-Otschir D, Voigt A, Schroter F, Prozorovski T, Lange N, Steffen J, Rieger M et al (2010) Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell 142: 613–624
56. Spur EM, Althof N, Respondek D, Klingel K, Heuser A, Overkleeft HS, Voigt A (2016) Inhibition of chymotryptic-like standard proteasome activity exacerbates doxorubicin-induced cytotoxicity in primary cardiomyocytes. Toxicology 353–354: 34–47
57. Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hajek R, Rosinol L, Siegel DS, Mihaylov GG et al (2015) Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 372: 142–152
58. Szalay G, Meiners S, Voigt A, Lauber J, Spieth C, Speer N, Sauter M, Kuckelkorn U, Zell A, Klingel K et al (2006) Ongoing coxsackievirus myocarditis is associated with increased formation and activity of myocardial immunoproteasomes. Am J Pathol 168: 1542–1552
59. Tu L, Moriya C, Imai T, Ishida H, Tetsutani K, Duan XF, Murata S, Tanaka K, Shimokawa C, Hisaeda H et al (2009) Critical role for the immunoproteasome subunit LMP7 in the resistance of mice to Toxoplasma gondii infection. Eur J Immunol 39: 3385–3394
60. Voigt A, Jakel S, Textoris-Taube K, Keller C, Drung I, Szalay G, Klingel K, Henklein P, Stangl K, Kloetzel PM et al (2010) Generation of in silico predicted coxsackievirus B3-derived MHC class I epitopes by proteasomes. Amino Acids 39: 243–255
61. Wessely R, Klingel K, Knowlton KU, Kandolf R (2001) Cardioselective infection with coxsackievirus B3 requires intact type I interferon signaling – implications for mortality and early viral replication. Circulation 103: 756–761