, Volume 40, Issue 1, pp 21–41 | Cite as

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

  • Angèle NalbandianEmail author
  • Arif A. Khan
  • Ruchi Srivastava
  • Katrina J. Llewellyn
  • Baichang Tan
  • Nora Shukr
  • Yasmin Fazli
  • Virginia E. Kimonis
  • Lbachir BenMohamedEmail author


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.


NLRP3 inflammasome macrophage valosin-containing protein myopathy 



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.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Angèle Nalbandian
    • 1
    • 2
    • 3
    Email author
  • Arif A. Khan
    • 1
  • Ruchi Srivastava
    • 1
  • Katrina J. Llewellyn
    • 2
  • Baichang Tan
    • 2
  • Nora Shukr
    • 1
  • Yasmin Fazli
    • 1
  • Virginia E. Kimonis
    • 2
  • Lbachir BenMohamed
    • 1
    • 4
    • 5
    Email author
  1. 1.Laboratory of Cellular and Molecular Immunology, Gavin Herbert Institute, School of MedicineUniversity of California IrvineIrvineUSA
  2. 2.Division of Genetics and Genomics Medicine, Department of PediatricsUniversity of California IrvineIrvineUSA
  3. 3.Division of Genetics and Metabolism, Department of PediatricsUniversity of California IrvineIrvineUSA
  4. 4.Department of Molecular Biology and Biochemistry, School of MedicineUniversity of California IrvineIrvineUSA
  5. 5.Institute for Immunology, School of MedicineUniversity of California IrvineIrvineUSA

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