Skip to main content
SpringerLink
Log in

Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy

  • ORIGINAL ARTICLE
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Aberrant activation of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, triggers a pathogenic inflammatory response in many inherited neurodegenerative disorders. Inflammation has recently been associated with valosin-containing protein (VCP)-associated diseases, caused by missense mutations in the VCP gene. This prompted us to investigate whether NLRP3 inflammasome plays a role in VCP-associated diseases, which classically affects the muscles, bones, and brain. In this report, we demonstrate (i) an elevated activation of the NLRP3 inflammasome in VCP myoblasts, derived from induced pluripotent stem cells (iPSCs) of VCP patients, which was significantly decreased following in vitro treatment with the MCC950, a potent and specific inhibitor of NLRP3 inflammasome; (ii) a significant increase in the expression of NLRP3, caspase 1, IL-1β, and IL-18 in the quadriceps muscles of VCPR155H/+ heterozygote mice, an experimental mouse model that has many clinical features of human VCP-associated myopathy; (iii) a significant increase of number of IL-1β(+)F4/80(+)Ly6C(+) inflammatory macrophages that infiltrate the muscles of VCPR155H/+ mice; (iv) NLRP3 inflammasome activation and accumulation IL-1β(+)F4/80(+)Ly6C(+) macrophages positively correlated with high expression of TDP-43 and p62/SQSTM1 markers of VCP pathology in damaged muscle; and (v) treatment of VCPR155H/+ mice with MCC950 inhibitor suppressed activation of NLRP3 inflammasome, reduced the F4/80(+)Ly6C(+)IL-1β(+) macrophage infiltrates in the muscle, and significantly ameliorated muscle strength. Together, these results suggest that (i) NLRP3 inflammasome and local IL-1β(+)F4/80(+)Ly6C(+) inflammatory macrophages contribute to pathogenesis of VCP-associated myopathy and (ii) identified MCC950 specific inhibitor of the NLRP3 inflammasome with promising therapeutic potential for the treatment of VCP-associated myopathy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Bauernfeind, F., A. Ablasser, E. Bartok, S. Kim, J. Schmid-Burgk, T. Cavlar, and V. Hornung. 2011. Inflammasomes: current understanding and open questions. Cellular and Molecular Life Sciences 68: 765–783.

    Article  CAS  PubMed  Google Scholar 

  2. Cassel, S.L., S. Joly, and F.S. Sutterwala. 2009. The NLRP3 inflammasome: a sensor of immune danger signals. Seminars in Immunology 21: 194–198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cook, G.P., S. Savic, M. Wittmann, and M.F. McDermott. 2010. The NLRP3 inflammasome, a target for therapy in diverse disease states. European Journal of Immunogenetics 40: 631–634.

    Article  CAS  Google Scholar 

  4. Schroder, K., R. Zhou, and J. Tschopp. 2010. The NLRP3 inflammasome: a sensor for metabolic danger? Science 327: 296–300.

    Article  CAS  PubMed  Google Scholar 

  5. Strowig, T., J. Henao-Mejia, E. Elinav, and R. Flavell. 2012. Inflammasomes in health and disease. Nature 481: 278–286.

    Article  CAS  PubMed  Google Scholar 

  6. Heneka, M.T., M.P. Kummer, and E. Latz. 2014. Innate immune activation in neurodegenerative disease. Nature Reviews Immunology 14: 463–477.

    Article  CAS  PubMed  Google Scholar 

  7. Saresella, M., F. Piancone, I. Marventano, M. Zoppis, A. Hernis, M. Zanette, D. Trabattoni, M. Chiappedi, A. Ghezzo, M.P. Canevini, et al. 2016. Multiple inflammasome complexes are activated in autistic spectrum disorders. Brain Behav Immun.

  8. Taga, M., T. Minett, J. Classey, F.E. Matthews, C. Brayne, P.G. Ince, J.A. Nicoll, J. Hugon, D. Boche, C. Mrc. 2016. Metaflammasome components in the human brain: a role in dementia with alzheimer’s pathology? Brain Pathol.

  9. Couturier, J., I.C. Stancu, O. Schakman, N. Pierrot, F. Huaux, P. Kienlen-Campard, I. Dewachter, and J.N. Octave. 2016. Activation of phagocytic activity in astrocytes by reduced expression of the inflammasome component ASC and its implication in a mouse model of Alzheimer disease. Journal of Neuroinflammation 13: 20.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Freeman, L.C., and J.P. Ting. 2016. The pathogenic role of the inflammasome in neurodegenerative diseases. Journal of Neurochemistry 136(Suppl 1): 29–38.

    Article  CAS  PubMed  Google Scholar 

  11. Schmid-Burgk, J.L., D. Chauhan, T. Schmidt, T.S. Ebert, J. Reinhardt, E. Endl, and V. Hornung. 2016. A genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) screen identifies NEK7 as an essential component of NLRP3 inflammasome activation. The Journal of Biological Chemistry 291: 103–109.

    Article  CAS  PubMed  Google Scholar 

  12. Olsen, I., and S.K. Singhrao. 2016. Inflammasome involvement in Alzheimer’s disease. Journal of Alzheimer’s Disease 54: 45–53.

    Article  CAS  PubMed  Google Scholar 

  13. Kimonis, V.E., E. Fulchiero, J. Vesa, and G. Watts. 2008. VCP disease associated with myopathy, Paget disease of bone and frontotemporal dementia: review of a unique disorder. Biochimica et Biophysica Acta 1782: 744–748.

    Article  CAS  PubMed  Google Scholar 

  14. Kimonis, V.E., S.G. Mehta, E.C. Fulchiero, D. Thomasova, M. Pasquali, K. Boycott, E.G. Neilan, A. Kartashov, M.S. Forman, S. Tucker, et al. 2008. Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia. American Journal of Medical Genetics. Part A 146A: 745–757.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Neumann, M., I.R. Mackenzie, N.J. Cairns, P.J. Boyer, W.R. Markesbery, C.D. Smith, J.P. Taylor, H.A. Kretzschmar, V.E. Kimonis, and M.S. Forman. 2007. TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. Journal of Neuropathology and Experimental Neurology 66: 152–157.

    Article  PubMed  Google Scholar 

  16. Watts, G.D., D. Thomasova, S.K. Ramdeen, E.C. Fulchiero, S.G. Mehta, D.A. Drachman, C.C. Weihl, Z. Jamrozik, H. Kwiecinski, A. Kaminska, and V.E. Kimonis. 2007. Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia. Clinical Genetics 72: 420–426.

    Article  CAS  PubMed  Google Scholar 

  17. Kimonis, V.E., M.J. Kovach, B. Waggoner, S. Leal, A. Salam, L. Rimer, K. Davis, R. Khardori, and D. Gelber. 2000. Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone. Genetics in Medicine 2: 232–241.

    Article  CAS  PubMed  Google Scholar 

  18. Dec, E., P. Rana, V. Katheria, R. Dec, M. Khare, A. Nalbandian, S.Y. Leu, S. Radom-Aizik, K. Llewellyn, L. BenMohamed, et al. 2014. Cytokine profiling in patients with VCP-associated disease. Clinical and Translational Science 7: 29–32.

    Article  CAS  PubMed  Google Scholar 

  19. Roca, I., J. Requena, M.J. Edel, and A.B. Alvarez-Palomo. 2015. Myogenic precursors from iPS cells for skeletal muscle cell replacement therapy. Journal of Clinical Medicine 4: 243–259.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Salani, S., C. Donadoni, F. Rizzo, N. Bresolin, G.P. Comi, and S. Corti. 2012. Generation of skeletal muscle cells from embryonic and induced pluripotent stem cells as an in vitro model and for therapy of muscular dystrophies. Journal of Cellular and Molecular Medicine 16: 1353–1364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Llewellyn, K.J., A. Nalbandian, K.M. Jung, C. Nguyen, A. Avanesian, T. Mozaffar, D. Piomelli, and V.E. Kimonis. 2014. Lipid-enriched diet rescues lethality and slows down progression in a murine model of VCP-associated disease. Human Molecular Genetics 23: 1333–1344.

    Article  CAS  PubMed  Google Scholar 

  22. R.M. Deacon 2013. Measuring the strength of mice. J Vis Exp.

  23. Capers, P.L., H.I. Hyacinth, S. Cue, P. Chappa, T. Vikulina, S. Roser-Page, M.N. Weitzmann, D.R. Archer, G.W. Newman, A. Quarshie, et al. 2015. Body composition and grip strength are improved in transgenic sickle mice fed a high-protein diet. Journal of Nutritional Science 4: e6.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Nevins, M.E., S.A. Nash, and P.M. Beardsley. 1993. Quantitative grip strength assessment as a means of evaluating muscle relaxation in mice. Psychopharmacology 110: 92–96.

    Article  CAS  PubMed  Google Scholar 

  25. Wolf, E., R. Wanke, E. Schenck, W. Hermanns, and G. Brem. 1995. Effects of growth hormone overproduction on grip strength of transgenic mice. European Journal of Endocrinology 133: 735–740.

    Article  CAS  PubMed  Google Scholar 

  26. Nalbandian, A., K.J. Llewellyn, M. Badadani, H.Z. Yin, C. Nguyen, V. Katheria, G. Watts, J. Mukherjee, J. Vesa, V. Caiozzo, et al. 2013. A progressive translational mouse model of human valosin-containing protein disease: the VCP(R155H/+) mouse. Muscle and Nerve 47: 260–270.

    Article  CAS  PubMed  Google Scholar 

  27. Nalbandian, A., C. Nguyen, V. Katheria, K.J. Llewellyn, M. Badadani, V. Caiozzo, and V.E. Kimonis. 2013. Exercise training reverses skeletal muscle atrophy in an experimental model of VCP disease. PLoS One 8: e76187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang, X., A.A. Chentoufi, G. Dasgupta, A.B. Nesburn, M. Wu, X. Zhu, D. Carpenter, S.L. Wechsler, S. You, and L. BenMohamed. 2009. A genital tract peptide epitope vaccine targeting TLR-2 efficiently induces local and systemic CD8+ T cells and protects against herpes simplex virus type 2 challenge. Mucosal Immunology 2: 129–143.

    Article  CAS  PubMed  Google Scholar 

  29. Uchida, A., H. Sasaguri, N. Kimura, M. Tajiri, T. Ohkubo, F. Ono, F. Sakaue, K. Kanai, T. Hirai, T. Sano, et al. 2012. Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43. Brain 135: 833–846.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Xu, Z., and C. Yang. 2014. TDP-43—the key to understanding amyotrophic lateral sclerosis. Rare Diseases 2: e944443.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wils, H., G. Kleinberger, J. Janssens, S. Pereson, G. Joris, I. Cuijt, V. Smits, C. Ceuterick-de Groote, C. Van Broeckhoven, and S. Kumar-Singh. 2010. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proceedings of the National Academy of Sciences of the United States of America 107: 3858–3863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Geser, F., D. Prvulovic, L. O’Dwyer, O. Hardiman, P. Bede, A.L. Bokde, J.Q. Trojanowski, and H. Hampel. 2011. On the development of markers for pathological TDP-43 in amyotrophic lateral sclerosis with and without dementia. Progress in Neurobiology 95: 649–662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Coll, R.C., A.A. Robertson, J.J. Chae, S.C. Higgins, R. Munoz-Planillo, M.C. Inserra, I. Vetter, L.S. Dungan, B.G. Monks, A. Stutz, et al. 2015. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature Medicine 21: 248–255.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Nalbandian, A., K.J. Llewellyn, M. Kitazawa, H.Z. Yin, M. Badadani, N. Khanlou, R. Edwards, C. Nguyen, J. Mukherjee, T. Mozaffar, et al. 2012. The homozygote VCP(R(1)(5)(5)H/R(1)(5)(5)H) mouse model exhibits accelerated human VCP-associated disease pathology. PLoS One 7: e46308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Badadani, M., A. Nalbandian, G.D. Watts, J. Vesa, M. Kitazawa, H. Su, J. Tanaja, E. Dec, D.C. Wallace, J. Mukherjee, et al. 2010. VCP associated inclusion body myopathy and paget disease of bone knock-in mouse model exhibits tissue pathology typical of human disease. PLoS One 5.

  36. Gross, C.J., and O. Gross. 2015. The Nlrp3 inflammasome admits defeat. Trends in Immunology 36: 323–324.

    Article  CAS  PubMed  Google Scholar 

  37. Dalakas, M.C. 2014. Mechanistic effects of IVIg in neuroinflammatory diseases: conclusions based on clinicopathologic correlations. Journal of Clinical Immunology 34(Suppl 1): S120–S126.

    Article  PubMed  Google Scholar 

  38. Grunblatt, E., S. Mandel, and M.B. Youdim. 2000. Neuroprotective strategies in Parkinson’s disease using the models of 6-hydroxydopamine and MPTP. The Annals of the New York Academy of Sciences 899: 262–273.

    Article  CAS  PubMed  Google Scholar 

  39. Tuon, T., P.S. Souza, M.F. Santos, F.T. Pereira, G.S. Pedroso, T.F. Luciano, C.T. De Souza, R.C. Dutra, P.C. Silveira, and R.A. Pinho. 2015. Physical training regulates mitochondrial parameters and neuroinflammatory mechanisms in an experimental model of Parkinson’s disease. Oxidative Medicine and Cellular Longevity 2015: 261809.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Kovach, M.J., B. Waggoner, S.M. Leal, D. Gelber, R. Khardori, M.A. Levenstien, C.A. Shanks, G. Gregg, M.T. Al-Lozi, T. Miller, et al. 2001. Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Molecular Genetics and Metabolism 74: 458–475.

    Article  CAS  PubMed  Google Scholar 

  41. Watts, G.D., J. Wymer, M.J. Kovach, S.G. Mehta, S. Mumm, D. Darvish, A. Pestronk, M.P. Whyte, and V.E. Kimonis. 2004. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nature Genetics 36: 377–381.

    Article  CAS  PubMed  Google Scholar 

  42. Joassard, O.R., A. Amirouche, Y.S. Gallot, M.M. Desgeorges, J. Castells, A.C. Durieux, P. Berthon, and D.G. Freyssenet. 2013. Regulation of Akt-mTOR, ubiquitin-proteasome and autophagy-lysosome pathways in response to formoterol administration in rat skeletal muscle. International Journal of Biochemistry and Cell Biology 45: 2444–2455.

    Article  CAS  PubMed  Google Scholar 

  43. Tamura, Y., Y. Kitaoka, Y. Matsunaga, D. Hoshino, and H. Hatta. 2015. Daily heat stress treatment rescues denervation-activated mitochondrial clearance and atrophy in skeletal muscle. The Journal of Physiology 593: 2707–2720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nalbandian, A., K.J. Llewellyn, C. Nguyen, P.G. Yazdi, and V.E. Kimonis. 2015. Rapamycin and chloroquine: the in vitro and in vivo effects of autophagy-modifying drugs show promising results in valosin containing protein multisystem proteinopathy. PLoS One 10: e0122888.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Shen, Y.F., Y. Tang, X.J. Zhang, K.X. Huang, and W.D. Le. 2013. Adaptive changes in autophagy after UPS impairment in Parkinson’s disease. Acta Pharmacologica Sinica 34: 667–673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Halle, A., V. Hornung, G.C. Petzold, C.R. Stewart, B.G. Monks, T. Reinheckel, K.A. Fitzgerald, E. Latz, K.J. Moore, and D.T. Golenbock. 2008. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nature Immunology 9: 857–865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Heneka, M.T., M.P. Kummer, A. Stutz, A. Delekate, S. Schwartz, A. Vieira-Saecker, A. Griep, D. Axt, A. Remus, T.C. Tzeng, et al. 2013. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493: 674–678.

    Article  CAS  PubMed  Google Scholar 

  48. Singhal, G., E.J. Jaehne, F. Corrigan, C. Toben, and B.T. Baune. 2014. Inflammasomes in neuroinflammation and changes in brain function: a focused review. Frontiers in Neuroscience 8: 315.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Tan, M.S., J.T. Yu, T. Jiang, X.C. Zhu, and L. Tan. 2013. The NLRP3 inflammasome in Alzheimer’s disease. Molecular Neurobiology 48: 875–882.

    Article  CAS  PubMed  Google Scholar 

  50. Tan, M.S., J.T. Yu, T. Jiang, X.C. Zhu, H.F. Wang, W. Zhang, Y.L. Wang, W. Jiang, and L. Tan. 2013. NLRP3 polymorphisms are associated with late-onset Alzheimer’s disease in Han Chinese. Journal of Neuroimmunology 265: 91–95.

    Article  CAS  PubMed  Google Scholar 

  51. Fink, S.L., and B.T. Cookson. 2005. Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infection and Immunity 73: 1907–1916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mariathasan, S., K. Newton, D.M. Monack, D. Vucic, D.M. French, W.P. Lee, M. Roose-Girma, S. Erickson, and V.M. Dixit. 2004. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430: 213–218.

    Article  CAS  PubMed  Google Scholar 

  53. Heneka, M.T., M.J. Carson, J. El Khoury, G.E. Landreth, F. Brosseron, D.L. Feinstein, A.H. Jacobs, T. Wyss-Coray, J. Vitorica, R.M. Ransohoff, et al. 2015. Neuroinflammation in Alzheimer’s disease. Lancet Neurology 14: 388–405.

    Article  CAS  PubMed  Google Scholar 

  54. Broderick, L., D. De Nardo, B.S. Franklin, H.M. Hoffman, and E. Latz. 2015. The inflammasomes and autoinflammatory syndromes. Annual Review of Pathology 10: 395–424.

    Article  CAS  PubMed  Google Scholar 

  55. De Nardo, D., and E. Latz. 2011. NLRP3 inflammasomes link inflammation and metabolic disease. Trends in Immunology 32: 373–379.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Shao, B.Z., Z.Q. Xu, B.Z. Han, D.F. Su, and C. Liu. 2015. NLRP3 inflammasome and its inhibitors: a review. Frontiers in Pharmacology 6: 262.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Rawat, R., T.V. Cohen, B. Ampong, D. Francia, A. Henriques-Pons, E.P. Hoffman, and K. Nagaraju. 2010. Inflammasome up-regulation and activation in dysferlin-deficient skeletal muscle. The American Journal of Pathology 176: 2891–2900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lundberg, I., A.K. Kratz, H. Alexanderson, and M. Patarroyo. 2000. Decreased expression of interleukin-1alpha, interleukin-1beta, and cell adhesion molecules in muscle tissue following corticosteroid treatment in patients with polymyositis and dermatomyositis. Arthritis and Rheumatism 43: 336–348.

    Article  CAS  PubMed  Google Scholar 

  59. Tucci, M., C. Quatraro, F. Dammacco, and F. Silvestris. 2006. Interleukin-18 overexpression as a hallmark of the activity of autoimmune inflammatory myopathies. Clinical and Experimental Immunology 146: 21–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tucci, M., C. Quatraro, F. Dammacco, and F. Silvestris. 2007. Increased IL-18 production by dendritic cells in active inflammatory myopathies. The Annals of the New York Academy of Sciences 1107: 184–192.

    Article  CAS  PubMed  Google Scholar 

  61. Lunemann, J.D., J. Schmidt, D. Schmid, K. Barthel, A. Wrede, M.C. Dalakas, and C. Munz. 2007. Beta-amyloid is a substrate of autophagy in sporadic inclusion body myositis. Annals of Neurology 61: 476–483.

    Article  CAS  PubMed  Google Scholar 

  62. Schmidt, J., K. Barthel, A. Wrede, M. Salajegheh, M. Bahr, and M.C. Dalakas. 2008. Interrelation of inflammation and APP in sIBM: IL-1 beta induces accumulation of beta-amyloid in skeletal muscle. Brain 131: 1228–1240.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Schmidt, J., K. Barthel, J. Zschuntzsch, I.E. Muth, E.J. Swindle, A. Hombach, S. Sehmisch, A. Wrede, F. Luhder, R. Gold, and M.C. Dalakas. 2012. Nitric oxide stress in sporadic inclusion body myositis muscle fibres: inhibition of inducible nitric oxide synthase prevents interleukin-1beta-induced accumulation of beta-amyloid and cell death. Brain 135: 1102–1114.

    Article  PubMed  Google Scholar 

  64. Schaale, K., K.M. Peters, A.M. Murthy, A.K. Fritzsche, M.D. Phan, M. Totsika, A.A. Robertson, K.B. Nichols, M.A. Cooper, K.J. Stacey, et al. 2015. Strain- and host species-specific inflammasome activation, IL-1beta release, and cell death in macrophages infected with uropathogenic Escherichia coli. Mucosal Immunol.

  65. Sester, D.P., V. Sagulenko, S.J. Thygesen, J.A. Cridland, Y.S. Loi, S.O. Cridland, S.L. Masters, U. Genske, V. Hornung, C.E. Andoniou, et al. 2015. Deficient NLRP3 and AIM2 inflammasome function in autoimmune NZB mice. The Journal of Immunology 195: 1233–1241.

    Article  CAS  PubMed  Google Scholar 

  66. Sester, D.P., S.J. Thygesen, V. Sagulenko, P.R. Vajjhala, J.A. Cridland, N. Vitak, K.W. Chen, G.W. Osborne, K. Schroder, and K.J. Stacey. 2015. A novel flow cytometric method to assess inflammasome formation. The Journal of Immunology 194: 455–462.

    Article  CAS  PubMed  Google Scholar 

  67. Schroder, K., and J. Tschopp. 2010. The inflammasomes. Cell 140: 821–832.

    Article  CAS  PubMed  Google Scholar 

  68. Tschopp, J., and K. Schroder. 2010. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nature Reviews Immunology 10: 210–215.

    Article  CAS  PubMed  Google Scholar 

  69. Abderrazak, A., T. Syrovets, D. Couchie, K. El Hadri, B. Friguet, T. Simmet, and M. Rouis. 2015. NLRP3 inflammasome: from a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases. Redox Biology 4C: 296–307.

    Article  Google Scholar 

  70. Rathinam, V.A., S.K. Vanaja, L. Waggoner, A. Sokolovska, C. Becker, L.M. Stuart, J.M. Leong, and K.A. Fitzgerald. 2012. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell 150: 606–619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Vanaja, S.K, Rathinam, V.A, Fitzgerald, K.A. 2015. Mechanisms of inflammasome activation: recent advances and novel insights. Trends Cell Biol.

  72. Boyden, E.D., and W.F. Dietrich. 2006. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nature Genetics 38: 240–244.

    Article  CAS  PubMed  Google Scholar 

  73. Mawhinney, L.J., J.P. de Rivero Vaccari, G.A. Dale, R.W. Keane, and H.M. Bramlett. 2011. Heightened inflammasome activation is linked to age-related cognitive impairment in Fischer 344 rats. BMC Neuroscience 12: 123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Zhao, Y., J. Yang, J. Shi, Y.N. Gong, Q. Lu, H. Xu, L. Liu, and F. Shao. 2011. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477: 596–600.

    Article  CAS  PubMed  Google Scholar 

  75. Miao, E.A., C.M. Alpuche-Aranda, M. Dors, A.E. Clark, M.W. Bader, S.I. Miller, and A. Aderem. 2006. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nature Immunology 7: 569–575.

    Article  CAS  PubMed  Google Scholar 

  76. Miao, E.A., D.P. Mao, N. Yudkovsky, R. Bonneau, C.G. Lorang, S.E. Warren, I.A. Leaf, and A. Aderem. 2010. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proceedings of the National Academy of Sciences of the United States of America 107: 3076–3080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Silveira, T.N., and D.S. Zamboni. 2010. Pore formation triggered by Legionella spp. is an Nlrc4 inflammasome-dependent host cell response that precedes pyroptosis. Infection and Immunity 78: 1403–1413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Akhter, A., M.A. Gavrilin, L. Frantz, S. Washington, C. Ditty, D. Limoli, C. Day, A. Sarkar, C. Newland, J. Butchar, et al. 2009. Caspase-7 activation by the Nlrc4/Ipaf inflammasome restricts Legionella pneumophila infection. PLoS Pathogens 5: e1000361.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Martinon, F., V. Petrilli, A. Mayor, A. Tardivel, and J. Tschopp. 2006. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440: 237–241.

    Article  CAS  PubMed  Google Scholar 

  80. Hornung, V., A. Ablasser, M. Charrel-Dennis, F. Bauernfeind, G. Horvath, D.R. Caffrey, E. Latz, and K.A. Fitzgerald. 2009. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458: 514–518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Fernandes-Alnemri, T., J.W. Yu, P. Datta, J. Wu, and E.S. Alnemri. 2009. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458: 509–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Sokolovska, A., C.E. Becker, W.K. Ip, V.A. Rathinam, M. Brudner, N. Paquette, A. Tanne, S.K. Vanaja, K.J. Moore, K.A. Fitzgerald, et al. 2013. Activation of caspase-1 by the NLRP3 inflammasome regulates the NADPH oxidase NOX2 to control phagosome function. Nature Immunology 14: 543–553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Blum-Degen, D., L. Frolich, S. Hoyer, and P. Riederer. 1995. Altered regulation of brain glucose metabolism as a cause of neurodegenerative disorders? Journal of Neural Transmission. Supplementum 46: 139–147.

    CAS  PubMed  Google Scholar 

  84. Blum-Degen, D., T. Muller, W. Kuhn, M. Gerlach, H. Przuntek, and P. Riederer. 1995. Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neuroscience Letters 202: 17–20.

    Article  CAS  PubMed  Google Scholar 

  85. Franchi, L., A. Amer, M. Body-Malapel, T.D. Kanneganti, N. Ozoren, R. Jagirdar, N. Inohara, P. Vandenabeele, J. Bertin, A. Coyle, et al. 2006. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in Salmonella-infected macrophages. Nature Immunology 7: 576–582.

    Article  CAS  PubMed  Google Scholar 

  86. Kummer, J.A., R. Broekhuizen, H. Everett, L. Agostini, L. Kuijk, F. Martinon, R. van Bruggen, and J. Tschopp. 2007. Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response. The Journal of Histochemistry and Cytochemistry 55: 443–452.

    Article  CAS  PubMed  Google Scholar 

  87. Martinon, F., and J. Tschopp. 2007. Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death and Differentiation 14: 10–22.

    Article  CAS  PubMed  Google Scholar 

  88. Karni, A., D.N. Koldzic, P. Bharanidharan, S.J. Khoury, and H.L. Weiner. 2002. IL-18 is linked to raised IFN-gamma in multiple sclerosis and is induced by activated CD4(+) T cells via CD40-CD40 ligand interactions. Journal of Neuroimmunology 125: 134–140.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the patients for providing the muscle biopsies used in this study, Dr. John R. Lukens, Department of Immunology, St Jude Children’s Research Hospital, Memphis, TN 38105, USA, and Vivien l Maltez, University of North Carolina at Chapel Hill, Department of Microbiology and Immunology for the help with inflammasome experiments and critical discussion.

Author information

Authors and Affiliations

  1. Laboratory of Cellular and Molecular Immunology, Gavin Herbert Institute, School of Medicine, University of California Irvine, Irvine, CA, 92697, USA

    Angèle Nalbandian, Arif A. Khan, Ruchi Srivastava, Nora Shukr, Yasmin Fazli & Lbachir BenMohamed

  2. Division of Genetics and Genomics Medicine, Department of Pediatrics, University of California Irvine, Irvine, CA, 92697, USA

    Angèle Nalbandian, Katrina J. Llewellyn, Baichang Tan & Virginia E. Kimonis

  3. Division of Genetics and Metabolism, Department of Pediatrics, University of California Irvine, Irvine, CA, USA

    Angèle Nalbandian

  4. Department of Molecular Biology and Biochemistry, School of Medicine, University of California Irvine, Irvine, CA, 92697, USA

    Lbachir BenMohamed

  5. Institute for Immunology, School of Medicine, University of California Irvine, Irvine, CA, 92697, USA

    Lbachir BenMohamed

Authors
  1. Angèle Nalbandian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arif A. Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ruchi Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Katrina J. Llewellyn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Baichang Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nora Shukr
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasmin Fazli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Virginia E. Kimonis
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lbachir BenMohamed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Angèle Nalbandian or Lbachir BenMohamed.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

This work is supported by Public Health Service research grants from National Institutes of Health/NIAMS R56AR066970 (VEK) and EY14900, EY019896, and EY024618 (LBM).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nalbandian, A., Khan, A.A., Srivastava, R. et al. Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy. Inflammation 40, 21–41 (2017). https://doi.org/10.1007/s10753-016-0449-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-016-0449-5

KEY WORDS

Search

Navigation