Inflammasomes: mediators of immune defence but culprits in inflammatory disease
During injury or infection, our body’s immune system protects us by launching inflammation.
But uncontrolled inflammation drives diseases such as gout, diabetes, neurodegenerative disease and cancer.
The Inflammasome Lab is defining the molecular and cellular processes of inflammation.
We seek to unravel the secrets of inflammasomes – protein complexes at the heart of inflammation and disease – to allow for new therapies to fight human diseases.
Group leader
Professor Kate Schroder
Group Leader, Inflammasomes: mediators of immune defence but culprits in inflammatory disease
+61 7 3346 2058
k.schroder@uq.edu.au
IMB Experts Profile
Centre for Inflammation and Disease Research
Inflammasome and caspase activation mechanisms and cellular programs.
Inflammasomes activate caspase family proteases, and thereby trigger caspase-dependent cellular programs, such as cytokine maturation and secretion, pyroptotic cell death and apoptotic cell death. We aim to understand precisely how inflammasomes control the activity of caspases, and the proteolytic cascades that control cellular programs such as unconventional protein secretion.
Inflammasome inhibition by cellular pathways and small molecules.
Inflammasomes are potent drivers of inflammatory responses, and are thus important for microbial clearance. But uncontrolled or inappropriate inflammatory responses are responsible for a wide variety of human diseases (e.g. septic shock, gout, diabetes, neurodegenerative diseases, various cancers). We are characterising cellular mechanisms of inflammasome inhibition, of key importance to maintaining human health. We are also characterising new pharmacological approaches for inflammasome inhibition, with broad potential for the treatment of human inflammatory and neurodegenerative diseases.
Inflammasome function in neutrophils.
Neutrophils are innate immune cells with key functions in antimicrobial host defence, but their ability to signal via pattern recognition receptor pathways is poorly characterised. We are characterising new roles for neutrophils in inflammasome signalling in vivo, and seek to understand how cell identity shapes neutrophil immune signalling pathways.
Host-pathogen interactions.
The inflammasome pathway is an important part of the host defence response to infection, and so microbes have evolved various mechanisms to evade this response. We are defining how inflammasomes detect microbes, and the microbial strategies employed to avoid this antimicrobial response.
Inflammasome function in humans.
Immunological research often uses the laboratory mouse to understand human disease. Inflammasome research is no exception, and previous studies in mice have revealed important mechanisms of immune signalling. But the immune responses of humans and mice are not identical, in part because of gene differences between these species. Recent technological advances (e.g. CRISPR/Cas9 gene editing) give us unprecedented precision in approaches for characterising inflammasome signalling in human cells.
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:
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
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
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).