Investigating how the immunosuppressant Cyclosporin A inhibits NLRP3 inflammasome activation  — ASN Events
  1. Schedule
  2. Poster Session 2
  3. Investigating how the immunosuppressant Cyclosporin A inhibits NLRP3 inflammasome activation 

Investigating how the immunosuppressant Cyclosporin A inhibits NLRP3 inflammasome activation  (#190)

Swarna Lekha Vijayaraj 1
  1. Walter and Eliza Hall Institute, Carlton, VIC, Australia

Caspase-1 associated with the NLRP3 inflammasome cleaves and thereby activates the pro-inflammatory cytokines IL-1b and IL-18(1). NLRP3-caspase-1 promotes immune responses to microbial infection, but is also pathologically activated in diseases such as gout, diabetes and cryopyrin-associated autoinflammatory syndromes(2). The mechanisms of NLRP3 activation remain controversial, but recent studies have suggested that defects in mitochondrial homeostasis are responsible for NLRP3 activation(3, 4). Cyclosporin A inhibits NLRP3 activation (5, 6). It has been proposed that because cyclosporin A targets cyclophilin D to prevent mitochondrial permeability transition pore  (MPT) opening, that MPT is required for NLRP3 functioning. We observed, however, that deletion of cyclophilin D did not prevent NLRP3 activation, and that cyclosporin A still inhibited NLRP3 in cyclophilin D deficient macrophages. Here we investigate other cyclosporin A targets to identify how cyclosporin A potently shuts down NLRP3 activity, and uncover novel proteins essential of NLRP3-driven immune responses.

  1. F. Martinon, A. Mayor, J. Tschopp, in Annual Review of Immunology. (Annual Reviews, Palo Alto, 2009), vol. 27, pp. 229-265.
  2. P. Menu, J. E. Vince, The NLRP3 inflammasome in health and disease: the good, the bad and the ugly. Clinical and Experimental Immunology 166, 1 (Oct, 2011).
  3. K. Shimada et al., Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome during Apoptosis. Immunity 36, 401 (Mar, 2012).
  4. R. B. Zhou, A. S. Yazdi, P. Menu, J. Tschopp, A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221 (Jan, 2011)
  5. S. S. Iyer et al., Mitochondrial Cardiolipin Is Required for Nlrp3 Inflammasome Activation. Immunity 39, 311 (Aug, 2013).
  6. K. Nakahira et al., Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nature Immunology 12, 222 (Mar, 2011).