Inflammasomes: mediators of immune defence but culprits in inflammatory disease

Research title: Inflammasomes in infection and inflammatory disease

Summary of research interests: The innate immune system is critical to defence against infection, but also drives unhealthy processes in inflammatory disease. An important emerging player in innate immunity is the ‘inflammasome’ pathway. Inflammasomes are molecular machines that trigger cytokine maturation and immune system activation in response to signals indicating cellular ‘danger’. While the inflammasome pathway is critical for host defence against infection, it is also a key driver of unhealthy inflammation in many human diseases. We use a wide variety of molecular and cell biology techniques, in conjunction with animal models and human clinical samples, to investigate the biology of inflammasomes in host defence and inflammatory disease at the molecular, cellular and organismal levels.

Traineeships, honours and PhD projects include

• Inflammasome activation mechanisms
• Human-specific inflammasome and caspase pathways
• Pathogenic inflammasome function in human diseases
• Inflammasome inhibition by small molecule drugs and cellular pathways
• Neutrophil inflammasome function during infection and disease.

Contact: Professor Kate Schroder

+61 7 3346 2058
k.schroder@uq.edu.au

Find out more about Research Training at IMB:

Research Training

• Journal Article: Familial auto inflammation with neutrophilic dermatosis reveals a novel regulatory mechanism of pyrin activation

  Masters, Seth L., Lagou, Vasiliki, Jéru, Isabelle, Baker, Paul J., Van Eyck, Lien, Parry, David A., Lawless, Dylan, De Nardo, Dominic, Garcia-Perez, Josselyn E., Dagley, Laura F., Holley, Caroline L., Dooley, James, Moghaddas, Fiona, Pasciuto, Emanuela, Jeandel, Pierre-Yves, Sciot, Raf, Lyras, Dena, Webb, Andrew I., Nicholson, Sandra E., De Somer, Lien, van Nieuwenhove, Erika, Ruuth-Praz, Julia, Copin, Bruno, Cochet, Emmanuelle, Medlej-Hashim, Myrna, Megarbane, Andre, Schroder, Kate, Savic, Sinisa, Goris, An, Amselem, Serge, Wouters, Carine and Liston, Adrian (2016) Familial auto inflammation with neutrophilic dermatosis reveals a novel regulatory mechanism of pyrin activation. Science Translational Medicine, 8 332: 1-9. doi:10.1126/scitranslmed.aaf1471

• Journal Article: Sterile signals generate weaker and delayed macrophage NLRP3 inflammasome responses relative to microbial signals

  Bezbradica, Jelena S., Coll, Rebecca C. and Schroder, Kate (2016) Sterile signals generate weaker and delayed macrophage NLRP3 inflammasome responses relative to microbial signals. Cellular and Molecular Immunology, 1-9. doi:doi:10.1038/cmi.2016.11

• Journal Article: The murine neutrophil NLRP3 inflammasome is activated by soluble but not particulate or crystalline agonists

  Chen, Kaiwen W., Bezbradica, Jelena S., Gross, Christina J., Wall, Adam A., Sweet, Matthew J., Stow, Jennifer L. and Schroder, Kate (2016) The murine neutrophil NLRP3 inflammasome is activated by soluble but not particulate or crystalline agonists. European Journal of Immunology, 46 4: 1004-1010. doi:10.1002/eji.201545943

• Journal Article: NLRP12 is a neutrophil-specific, negative regulator of in vitro cell migration but does not modulate LPS- or infection-induced NF-κB or ERK signalling

  Zamoshnikova, Alina, Grob, Christina J., Schuster, Steffen, Chen, Kaiwen W., Wilson, Anne, Tacchini-Cottier, Fabienne and Schroder, Kate (2016) NLRP12 is a neutrophil-specific, negative regulator of in vitro cell migration but does not modulate LPS- or infection-induced NF-κB or ERK signalling. Immunobiology, 221 2: 341-346. doi:10.1016/j.imbio.2015.10.001

• Journal Article: NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5

  Baker, Paul J., Boucher, Dave, Bierschenk, Damien, Tebartz, Christina, Whitney, Paul G., D'Silva, Damian B, Tanzer, Marco J., Monteleone, Mercedes, Robertson, Avril A.B., Cooper, Matthew A., Alvarez-Diaz, Silvia, Herold, Marco J., Bedoui, Sammy, Schroder, Kate and Masters, Seth L. (2015) NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5. European Journal of Immunology, 45 10: 2918-2926. doi:10.1002/eji.201545655

• Journal Article: A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases

  Coll, Rebecca C., Robertson, Avril A. B., Chae, Jae Jin, Higgins, Sarah C., Muñoz-Planillo, Raúl, Inserra, Marco C., Vetter, Irina, Dungan, Lara S., Monks, Brian G., Stütz, Andrea, Croker, Daniel E., Butler, Mark S., Haneklaus, Moritz, Sutton, Caroline E., Núñez, Gabriel, Latz, Eicke, Kästner, Daniel L., Mills, Kingston H. G., Masters, Seth L., Schroder, Kate, Cooper, Matthew A. and O'Neill, Luke A. J. (2015) A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature Medicine, 21 3: 248-257. doi:10.1038/nm.3806

• Journal Article: The Neutrophil NLRC4 Inflammasome Selectively Promotes IL-1β Maturation without Pyroptosis during Acute Salmonella Challenge

  Chen, Kaiwen W., Groß, Christina J., Vasquez Sotomayor, Flor, Stacey, Katryn J., Tschopp, Jurg, Sweet, Matthew J. and Schroder, Kate (2014) The Neutrophil NLRC4 Inflammasome Selectively Promotes IL-1β Maturation without Pyroptosis during Acute Salmonella Challenge. Cell Reports, 8 2: 570-582. doi:10.1016/j.celrep.2014.06.028

• Journal Article: Acute lipopolysaccharide priming boosts inflammasome activation independently of inflammasome sensor induction

  Schroder, Kate, Sagulenko, Vitaliya, Zamoshnikova, Alina, Richards, Ayanthi A., Cridland, Jasmyn A., Irvine, Katharine M., Stacey, Katryn J. and Sweet, Matthew J. (2012) Acute lipopolysaccharide priming boosts inflammasome activation independently of inflammasome sensor induction. Immunobiology, 217 12: 1325-1329. doi:10.1016/j.imbio.2012.07.020

• Journal Article: Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages

  Schroder, Kate, Irvine, Katharine M., Taylor, Martin S., Bokil, Nilesh J., Le Cao, Kim-Anh, Masterman, Kelly-Anne, Labzin, Larisa I., Semple, Colin A., Kapetanovic, Ronan, Fairbairn, Lynsey, Akalin, Altuna, Faulkner, Geoffrey J., Baillie, John Kenneth, Gongora, Milena, Daub, Carsten O., Kawaji, Hideya, McLachlan, Geoffrey J., Goldman, Nick, Grimmond, Sean M., Carninci, Piero, Suzuki, Harukazu, Hayashizaki, Yoshihide, Lenhard, Boris, Hume, David A. and Sweet, Matthew J. (2012) Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages. Proceedings of the National Academy of Sciences of the USA, 109 16: E944-E953. doi:10.1073/pnas.1110156109

• Journal Article: NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production?

  Tschopp, Jurg and Schroder, Kate (2010) NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production?. Nature Reviews Immunology, 10 3: 210-215. doi:10.1038/nri2725

• Journal Article: The inflammasomes

  Schroder, Kate and Tschopp, Jurg (2010) The inflammasomes. Cell, 140 6: 821-832. doi:10.1016/j.cell.2010.01.040

• Journal Article: The NLRP3 inflammasome: a sensor for metabolic danger?

  Schroder, Kate, Zhou, Rongbin and Tschopp, Jurg (2010) The NLRP3 inflammasome: a sensor for metabolic danger?. Science, 327 5963: 269-300. doi:10.1126/science.1184003

• Journal Article: The regulated retrotransposon transcriptome of mammalian cells

  Faulkner, Geoffrey J., Kimura, Yasumasa, Daub, Carsten O., Wani, Shivangi, Plessy, Charles, Irvine, Katharine M., Schroder, Kate, Cloonan, Nicole, Steptoe, Anita L., Lassmann, Timo, Waki, Kazunori, Hornig, Nadine, Arakawa, Takahiro, Takahashi, Hazuki, Kawai, Jun, Forrest, Alistair R. R., Suzuki, Harukazu, Hayashizaki, Yoshihide, Hume, David A., Orlando, Valerio, Grimmond, Sean M. and Carninci, Piero (2009) The regulated retrotransposon transcriptome of mammalian cells. Nature genetics, 41 5: 563-571. doi:10.1038/ng.368

• Journal Article: The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line

  Suzuki, H, Forrest, ARR, van Nimwegen, E, Daub, CO, Balwierz, PJ, Irvine, KM, Lassmann, T, Ravasi, T, Hasegawa, Y, de Hoon, MJL, Katayama, S, Schroder, K, Carninci, P, Tomaru, Y, Kanamori-Katayama, M, Kubosaki, A, Akalin, A, Ando, Y, Arner, E, Asada, M, Asahara, H, Bailey, T, Bajic, VB, Bauer, D, Beckhouse, AG, Bertin, N, Bjorkegren, J, Brombacher, F, Bulger, E, Chalk, AM, Chiba, J, Cloonan, N, Dawe, A, Dostie, J, Engstrom, PG, Essack, M, Faulkner, GJ, Fink, JL, Fredman, D, Fujimori, K, Furuno, M, Gojobori, T, Gough, J, Grimmond, SM, Gustafsson, M, Hashimoto, M, Hashimoto, T, Hatakeyama, M, Heinzel, S, Hide, W, Hofmann, O, Hornquist, M, Huminiecki, L, Ikeo, K, Imamoto, N, Inoue, S, Inoue, Y, Ishihara, R, Iwayanagi, T, Jacobsen, A, Kaur, M, Kawaji, H, Kerr, MC, Kimura, R, Kimura, S, Kimura, Y, Kitano, H, Koga, H, Kojima, T, Kondo, S, Konno, T, Krogh, A, Kruger, A, Kumar, A, Lenhard, B, Lennartsson, A, Lindow, M, Lizio, M, MacPherson, C, Maeda, N, Maher, CA, Maqungo, M, Mar, J, Matigian, NA, Matsuda, H, Mattick, JS, Meier, S, Miyamoto, S, Miyamoto-Sato, E, Nakabayashi, K, Nakachi, Y, Nakano, M, Nygaard, S, Okayama, T, Okazaki, Y, Okuda-Yabukami, H, Orlando, V, Otomo, J, Pachkov, M, Petrovsky, N, Plessy, C, Quackenbush, J, Radovanovic, A, Rehli, M, Saito, R, Sandelin, A, Schmeier, S, Schonbach, C, Schwartz, AS, Semple, CA, Sera, M, Severin, J, Shirahige, K, Simons, C, Laurent, GS, Suzuki, M, Suzuki, T, Sweet, MJ, Taft, RJ, Takeda, S, Takenaka, Y, Tan, K, Taylor, MS, Teasdale, RD, Tegner, J, Teichmann, S, Valen, E, Wahlestedt, C, Waki, K, Waterhouse, A, Wells, Christine A., Winther, O, Wu, L, Yamaguchi, K, Yanagawa, H, Yasuda, J, Zavolan, M, Hume, DA, Arakawa, T, Fukuda, S, Imamura, K, Kai, C, Kaiho, A, Kawashima, T, Kawazu, C, Kitazume, Y, Kojima, M, Miura, H, Murakami, K, Murata, M, Ninomiya, N, Nishiyori, H, Noma, S, Ogawa, C, Sano, T, Simon, C, Tagami, M, Takahashi, Y, Kawai, J, Hayashizaki, Y, FANTOM Consortium and Riken Omics Science Center (2009) The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line. Nature Genetics, 41 5: 553-562. doi:10.1038/ng.375

• Journal Article: Tiny RNAs associated with transcription start sites in animals

  Taft, RJ, Glazov, EA, Cloonan, N, Simons, C, Stephen, S, Faulkner, GJ, Lassmann, T, Forrest, ARR, Grimmond, SM, Schroder, K, Irvine, K, Arakawa, T, Nakamura, M, Kubosaki, A, Hayashida, K, Kawazu, C, Murata, M, Nishiyori, H, Fukuda, S, Kawai, J, Daub, CO, Hume, DA, Suzuki, H, Orlando, V, Carninci, P, Hayashizaki, Y and Mattick, JS (2009) Tiny RNAs associated with transcription start sites in animals. Nature Genetics, 41 5: 572-578. doi:10.1038/ng.312

• Journal Article: Differential effects of CpG DNA on IFN-beta induction and STAT1 activation in murine macrophages versus dendritic cells: Alternatively activated STAT1 negatively regulates TLR signaling in macrophages

  Schroder, K., Spille, M., Pilz, A., Lattin, J., Bode, K. A., Irvine, K. M., Burrows, A. D., Ravasi, T., Weighardt, H., Stacey, K. J., Decker, T., Hume, D. A., Dalpke, A. H. and Sweet, M. J. (2007) Differential effects of CpG DNA on IFN-beta induction and STAT1 activation in murine macrophages versus dendritic cells: Alternatively activated STAT1 negatively regulates TLR signaling in macrophages. Journal of Immunology, 179 6: 3495-3503.

• Journal Article: Interferon-gamma: an overview of signals, mechanisms and functions

  Schroder, Kate, Hertzog, Paul J., Ravasi, Timothy and Hume, David A. (2004) Interferon-gamma: an overview of signals, mechanisms and functions. Journal of Leukocyte Biology, 75 2: 163-189. doi:10.1189/jlb.0603252

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Our research focuses on understanding how immune cells launch healthy inflammation to fight infection and unhealthy inflammation to promote disease. By understanding exactly how the body fights infection, we can help identify new drug targets or vaccines to combat infectious disease, which causes 13 million deaths globally each year. By understanding how unhealthy inflammation is initiated, we can design new strategies for the treatment of common inflammatory and neurodegenerative diseases. For example, our recent multidisciplinary collaborations developed new small molecule inhibitors of the inflammasome, that are currently under commercialisation as novel anti-inflammatory compounds.

We collaborate nationally and internationally, and across research fields.

Major collaborators include:

• Prof Matthew Sweet (innate immunity, IMB)
• Prof Jenny Stow (cell biology, IMB)
• Prof Alpha Yap (epithelial defence, IMB)
• Prof Matthew Cooper (anti-inflammatory drug design, IMB)
• Prof Ben Hankamer (structural biology, IMB)
• Assoc Prof Trent Woodruff (neurodegenerative disease, The University of Queensland)
• Assoc Prof Katryn Stacey (inflammasomes and cell death, The University of Queensland)
• Dr James Vince (cell death, The Walter and Eliza Hall Institute)
• Dr Seth Masters (auto-inflammatory diseases, The Walter and Eliza Hall Institute)
• Prof Geoff Farrell (liver disease, The Canberra Hospital)
• Prof Vojo Deretic (autophagy, University of New Mexico)
• Dr Jelena Bezbradica (sterile inflammation, University of Oxford)
• Prof Luke O’Neill (inflammatory signalling, Trinity College Dublin).