IL-18 production from the NLRP1 inflammasome prevents obesity and metabolic syndrome — ASN Events
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IL-18 production from the NLRP1 inflammasome prevents obesity and metabolic syndrome (#366)

Seth Masters 1 2 3 , Andrew J Murphy 4 5 6 , Michael J Kraakman 4 6 , Helene L Kammoun 2 7 , Kate E Lawlor 2 7 , John M Wentworth 7 8 , Ajithkumar Vasanthakuma 7 9 , Motti Gerlic 10 , Ladina DiRago 7 11 , Louise Cengia 7 11 , Rachael M Lane 7 12 , Donald Metcalf 7 11 , James E Vince 2 7 , Leonard C Harrison 7 13 , Axel Kallies 7 9 , Benjamin T Kile 7 14 , Ben A Croker 15 , Mark A Febbraio 16
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  3. Department of Medical Biology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  4. Haematopoiesis and Leukocyte Biology, VIC
  5. Department of Immunology, Monash University, Melbourne, VIC, Australia
  6. These authors contributed equally, .
  7. Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia
  8. Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  9. Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  10. Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  11. Cancer and Hematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  12. Chemical Biology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  13. Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  14. Chemical Biology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  15. Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
  16. Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia

IL-18 is activated by Caspase-1 in inflammasome complexes, and has anti-obesity effects, however it is not known which inflammasome regulates this process. We found that mice lacking the NLRP1 inflammasome phenocopy mice lacking IL-18, with spontaneous obesity due to intrinsic lipid accumulation. This is exacerbated when the mice are fed a high-fat diet (HFD), but not when mice are fed a high-fat, restricted-energy diet. Furthermore, mice with an activating mutation in NLRP1, and hence increased IL-18, have decreased adiposity and are resistant to diet induced metabolic dysfunction. Feeding these mice a HFD further increased plasma IL-18 concentrations, and strikingly resulted in loss of adipose tissue mass and fatal cachexia, which could be prevented by genetic deletion of IL-18. Therefore NLRP1 is an innate immune sensor that functions in the context of metabolic stress to produce IL-18, preventing obesity and metabolic syndrome.