The body's immune system monitors infection or damage to our bodies. It uses special sensors to detect microbes or products of damaged tissues. Inflammasomes are an important family of such sensors. They become active following the sensing of damage and they drive the production of two important signals, the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, which act to wake up the inflammatory response in our bodies.

Inflammation normally leads to repair to damaged tissue. However, if inflammation becomes chronic, all kinds of inflammatory diseases can occur. There are several inflammasomes, but the most well studied and understood is called NLRP3. The NLRP3 inflammasome has been shown to be overactive in many inflammatory diseases, including gout, osteoarthritis, atherosclerosis and neurological disorders such as Alzheimer’s and Parkinson’s disease.

Clinically used anti-inflammatories drugs include biologic therapeutics that target the main product of the NLRP3 inflammasome, IL-1, such as recombinant IL-1 receptor antagonist anakinra (Kineret), the neutralizing IL-1β antibody canakinumab (Ilaris) and the decoy IL-1 receptor rilonacept (Arcalyst). Canakinumab has recently been shown to have pronounced clinically protective effects in cardiovascular disease, cancer and arthritis, highlighting the potential value of a small molecule inhibitor of NLRP3 which will prevent IL-1β production.

Our mission at Inflazome is to identify and develop potent, first-in-class, small molecule NLRP3 inhibitors as treatments of a broad range of inflammatory diseases. 

 

General Inflammasome Information

Taming the inflammasome.” Levy M, Thaiss CA, Elinav E. Nature Medicine. 2015 Mar;21(3):213-5. DOI: 10.1038/nm.3808

Inflammasome inhibition: putting out the fire.” Netea MG, Joosten LA. Cell Metab. 2015 Apr 7;21(4):513-4. DOI: 10.1016/j.cmet.2015.03.012

 

Publications Involving Inflazome Founders

“NLRP3-inflammasome inhibition prevents high fat and high sugar diets-induced heart damage through autophagy induction,” Luís E. Pavillard, Diego Cañadas-Lozano, Elísabet Alcocer-Gómez, Fabiola Marín-Aguilar, Sheila Pereira, Avril A. B. Robertson, Jordi Muntané, Bernhard Ryffel, Matthew A. Cooper, José L. Quiles, Pedro Bullón, Jesús Ruiz-Cabello and Mario D. Cordero, Oncotarget, 2017, DOI: 10.18632/oncotarget.20763

“Pharmacological inhibition of the NLRP3 inflammasome as a potential treatment for multiple sclerosis induced central neuropathic pain”, Nemat Khan, Andy Kuo, David A Brockman, Matthew A Cooper, Maree T Smith, Inflammopharmacology, 2017, DOI: https://doi.org/10.1007/s10787-017-0401-9

“Specific inhibition of NLRP3 in chikungunya disease reveals a role for inflammasomes in alphavirus-induced inflammation” Weiqiang Chen, Suan-Sin Foo, Ali Zaid, Terk-Shin Teng, Lara J. Herrero, Stefan Wolf, Kothila Tharmarajah, Luan D. Vu, Caryn van Vreden, Adam Taylor, Joseph R. Freitas, Rachel W. Li, Trent M. Woodruff, Richard Gordon, David M. Ojcius, Helder I. Nakaya, Thirumala-Devi Kanneganti, Luke A. J. O’Neill, Avril A. B. Robertson, Nicholas J. King, Andreas Suhrbier, Matthew A. Cooper, Lisa F. P. Ng & Suresh Mahalingam, Nature Microbiology, 2017, DOI: 10.1038/s41564-017-0015-4

"Sulfonylureas as concomitant insulin secretagogues and NLRP3 inflammasome inhibitors”, James R. Hill, Rebecca C. Coll, Nancy Sue, Janet C Reid, Jennifer Dou, Caroline L. Holley, Ruby Pelingon, Joshua B. Dickinson, Trevor J. Biden, Kate Schroder, Matthew A. Cooper, and Avril A. B. Robertson, Chem Med Chem, 2017, 12, 1-10, DOI: 10.1002/cmdc.201700270

“High fat diet-induced obesity promotes steroid-resistant asthma through an NLRP3 inflammasome-dependent mechanism”, James Pinkerton, Richard Kim, Jemma Mayall, Md Khadem Ali, Malcolm Starkey, Avril Robertson, Luke O'Neill, Matthew Cooper, Philip Hansbro, Jay Horvat, Respirology, 2017, 22, 65-66

“Lipocalin-2 induces NLRP3 inflammasome activation via HMGB1 induced TLR4 signaling in heart tissue of mice under pressure overload challenge”, Erfei Song, James Jahng, Lisa Chong, HyeKyoung Sung, Meng Han, Cuiting Luo, Donghai Wu, Stellar Boo, Boris Hinz, Matthew Cooper, Avril Robertson, Thorsten Berger, Tak Mak, Isaac George, P Christian Schulze, Yu Wang, Aimin Xu and Gary Sweeney, American Journal of Translational Research, 2017, 9, 6, 2723-2735

"Myeloid-derived miR-223 regulates intestinal in ammation via repression of the NLRP3 inflammasome", Viola Neudecker, Moritz Haneklaus, Owen Jensen, Ludmila Khailova, Joanne C. Masterson, Hazel Tye, Kathryn Biette, Paul Jedlicka, Kelley S. Brodsky, Mark E. Gerich, Matthias Mack, Avril A.B. Robertson, Matthew A. Cooper, Glenn T. Furuta, Charles A. Dinarello, Luke A. O’Neill, Holger K. Eltzschig, Seth L. Masters, Eóin N. McNamee, The Journal of Experimental Medicine, 2017, 214, 6, DOI: 10.1084/jem.2016046

"Specific inhibition of NLRP3 in chikungunya disease reveals a role for inflammasomes in alphavirus-induced inflammation", Weiqiang Chen, Suan-Sin Foo, Ali Zaid, Terk-Shin Teng, Lara J. Herrero, Stefan Wolf, Kothila Tharmarajah, Luan D. Vu, Caryn van Vreden, Adam Taylor, Joseph R. Freitas, Rachel W. Li, Trent M. Woodruff, Richard Gordon, David M.Ojcius, Helder I. Nakaya, Thirumala-Devi Kanneganti, Luke A. J. O’Neill, Avril A. B. Robertson, Nicholas J. King, Andreas Suhrbier, Matthew A. Cooper, Lisa F. P. Ng, Suresh Mahalingam, Nature Microbiology, 2017, DOI: 10.1038/s41564-017-0015-4 

"Sulfonylureas as Concomitant Insulin Secretagogues and NLRP3 Inflammasome Inhibitors", James R. Hill, Rebecca C. Coll, Nancy Sue, Janet C. Reid, Jennifer Dou, Caroline L. Holley, Ruby Pelingon, Joshua B. Dickinson, Trevor J. Biden, Kate Schroder, Matthew A. Cooper, Avril A. B. Robertson, ChemMedChem, 2017, 12, 1-10, DOI: 10.1002/cmdc.201700270 

"Role for NLRP3 inflammasome-mediated, IL-1β-dependent responses in severe, steroid-resistant asthma", Richard Y. Kim, James W. Pinkerton, Ama T. Essilfie, Avril A. B. Robertson, Katherine J. Baines, Alexandra C. Brown, Jemma R. Mayall, Md. Khadem Ali, Malcolm R. Starkey, Nicole G. Hansbro, Jeremy A. Hirota, Lisa G. Wood, Jodie L. Simpson, Darryl A. Knight, Peter A. Wark, Peter G. Gibson, Luke A. J. O’Neill, Matthew A. Cooper, Jay C. Horvat, Philip M. Hansbro, American Journal of Respiratory and Critical Care Medicine, 2017, 196, 3, 283-297, DOI: 10.1164/rccm.201609-1830OC

"Inflammasomes in the lung", James W. Pinkerton, Richard Y. Kim, Avril A.B. Robertson, Jeremy A. Hirota, Lisa G. Wood, Darryl A. Knight, Matthew A. Cooper, Luke A.J. O’Neill, Jay C. Horvat, Philip M. Hansbro, Molecular Immunology, 2017, 86, 44-55, DOI: 10.1016/j.molimm.2017.01.014 

"NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice", Auvro R. Mridha, Alexander Wree, Avril A.B. Robertson, Matthew M. Yeh, Casey D. Johnson, Derrick M. Van Rooyen, Fahrettin Haczeyni, Narci C.-H. Teoh, Christopher Savard, George N. Ioannou, Seth L. Masters, Kate Schroder, Matthew A. Cooper, Ariel E. Feldstein, Geoffrey C. Farrell, Journal of Hepatology, 2017, 66, (5), 1037-1046, DOI: 10.1016/j.jhep.2017.01.022  

"Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice", José J. Fuster, Susan MacLauchlan, María A. Zuriaga, Maya N. Polackal, Allison C. Ostriker, Raja Chakraborty, Chia-Ling Wu, Soichi Sano, Sujatha Muralidharan, Cristina Rius, Jacqueline Vuong, Sophia Jacob, Varsha Muralidhar, Avril A. B. Robertson, Matthew A. Cooper, Vicente Andrés, Karen K. Hirschi, Kathleen A. Martin, Kenneth Walsh, Science, 2017, 355, 842–847, DOI:10.1126/science.aag138

"Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-b and cognitive function in APP/PS1 mice", C. Dempsey, A. Rubio Araiz, K.J. Bryson, O. Finucane, C. Larkin, E.L. Mills, A.A.B. Robertson, M.A. Cooper, L.A.J. O’Neill, M.A. Lynch, Brain, Behavior, and Immunity, 2017, 61, 306–316, DOI: 10.1016/j.bbi.2016.12.014

"The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype", Ashley A. Basiorka, Kathy L. McGraw, Erika A. Eksioglu, Xianghong Chen, Joseph Johnson, Ling Zhang, Qing Zhang, Brittany A. Irvine, Thomas Cluzeau, David A. Sallman, Eric Padron, Rami Komrokji, Lubomir Sokol, Rebecca C. Coll, Avril A. B. Robertson, Matthew A. Cooper, John L. Cleveland, Luke A. O’Neill, Sheng Wei, Alan F. List,  BLOOD, 2016, 128, 25, DOI: 10.1182/blood-2016-07- 730556 

"Identification, Synthesis, and Biological Evaluation of the Major Human Metabolite of NLRP3 Inflammasome Inhibitor MCC950", Manohar Salla, Mark S. Butler, Ruby Pelingon, Geraldine Kaeslin, Daniel E. Croker, Janet C. Reid, Jong Min Baek, Paul V. Bernhardt, Elizabeth M. J. Gillam, Matthew A. Cooper, Avril A. B. Robertson, ACS Medicinal Chemistry Letters, 2016, 7, 1034-1038, DOI: 10.1021/acsmedchemlett.6b00198  

"IL-1β is an innate immune sensor of microbial proteolysis", Christopher N. LaRock, Jordan Todd, Doris L. LaRock, Joshua Olson, Avril A. Robertson, Matthew A. Cooper, Hal M. Hoffman, Victor Nizet, Science Immunology, 2016, 1 (2), pp.eaah3539,  DOI:10.1126/sciimmunol.aah3539

"NLRP3 inflammasome-mediated, IL-1β-dependent inflammatory responses drive steroid-resistant asthma", Jay Horvat, Richard Kim, James Pinkerton, Aam-Tawiah Essilfie, Avril Robertson, Katherine Baines, Jemma Mayall, Malcolm Starkey, Peter Wark, Peter Gibson, Luke O'Neill, Matthew A. Cooper, Philip Hansbro, European Respiratory Journal, 2016, 48. DOI: 10.1183/13993003.congress-2016.PA564

 “K+ Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria”, Christina J. Groß, Ritu Mishra, Katharina S. Schneider, Guillaume Me´dard, Jennifer Wettmarshausen, Daniela C. Dittlein, Hexin Shi, Oliver Gorka, Paul-Albert Koenig,Stephan Fromm, Giovanni Magnani, Tamara Cikovi, Lara Hartjes, Joachim Smollich, Avril A.B. Robertson, Matthew A. Cooper, Marc Schmidt-Supprian, Michael Schuster, Kate Schroder, Petr Broz, Claudia Traidl-Hoffmann, Bruce Beutler, Bernhard Kuster, Jurgen Ruland, Sabine Schneider, Fabiana Perocchi, and Olaf Groß, Immunity, 2016, 45 (4), DOI: 10.1016/j.immuni.2016.08.010

“Role of the NLRP3 inflammasome in a model of acute burn-induced pain”, Jennifer Deuis,, Kathleen Yin, Matthew Cooper, Kate Schroder, Irina Vetter, BURNS, 2016, DOI: 10.1016/j.burns.2016.09.001

“T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4+ T cells”, Giuseppina Arbore, Erin E West, Avril A Robertson, Andreas Klos, Trent Woodruff, Luke A O'Neill, Alan Sher, Warren Leonard, Pete Monk, Matthew A Cooper, Andrew Cope, Katrin Mayer-Barber, Helen J Lachmann, Claudia Kemper, Science, 2016, 352 (6292), DOI: 10.1126/science.aad1210 

“Human Monocytes Engage an Alternative Inflammasome Pathway”, Moritz M. Gaidt, Thomas S. Ebert, Dhruv Chauhan, Tobias Schmidt, Jonathan L. Schmid-Burgk, Francesca Rapino, Avril A. B. Robertson, Matthew A. Cooper and Veit Hornung; Immunity, 2016, DOI: 10.1016/j.immuni.2016.01.012

“The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction“, European Heart Journal, 2016, DOI: 10.1093/eurheartj/ehw247

“Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A virus infection via temporal inhibition“, Anita Pinar, Jennifer K Dowling, Julie L McAuley, Avril AB Robertson, Eicke Latz, Grant R Drummond, Matthew A Cooper, Michelle D Tate and Ashley Mansell, Scientific Reports, 2016, 6: 27912, DOI: 10.1038/srep27912

“A small molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases,” R.C. Coll, A.A.B. Robertson, J.J. Chae, S.C.. Higgins, R. Muñoz-Planillo, M.C.. Inserra, I. Vetter, L.S.. Dungan, B.G.. Monks, A. Stutz, D.E. Croker, M.S. Butler, M. Haneklaus, C.E. Sutton, G. Núñez, E. Latz, D.L. Kastner, K.H.G. Mills, S.L. Masters, K. Schroder, MA Cooper, L.A.J. O’Neill, Nature Medicine, 2015, 21, 248-255, DOI: 10.1038/NM.3806

“Inflammasomes in COPD and neutrophilic asthma”, Richard Y Kim, James W Pinkerton, Peter G Gibson, Matthew A. Cooper, Jay C Horvat, Philip M Hansbro, Thorax, 2015, 70 (12), 1199-1201, DOI: 10.1136/thoraxjnl-2014-206736

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

“Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice”, S.M. Krishnan, J.K. Dowling, Y.H. Ling, H. Diep, C.T. Chan, D. Ferens, M.M. Kett, A. Pinar, C.S. Samuel, A. Vinh, T.V. Arumugam, T.D. Hewitson, B.K. Kemp-Harper, A.A.B. Roberston, M.A. Cooper, E. Latz, A. Mansell, C.G. Sobey, G.R. Drummond. British J. Pharmacol., 2015, 173 (4), 752 – 765, DOI: 10.1111/bph.13230

“Strain- and host species-specific inflammasome activation, IL-1β release, and cell death in macrophages infected with uropathogenic Escherichia coli”, Kolja Schaale, Kate M. Peters, Anna K. Fritzsche, Minh-Duy Phan, Makrina Totsika, Avril A.B. Robertson, Katie B. Nichols, Matthew A. Cooper, Glen C. Ulett, Katryn J. Stacey, Kate Schroder, Mark A. Schembri, Matthew J Sweet. Mucosal Immunology, 2015, 9 (1), 124-136, DOI: 10.1038/mi.2015.44