Research Lectures at Nobel Forum 15 March, 16.30
Frontiers in inflammation research: from NLRP3 to metabolic reprogramming
Luke A.J. O’Neill
School of Biochemistry and Immunology
Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland https://www.tcd.ie/Biochemistry/research/l_o_neill.php
The discovery of the NLRP3 inflammasome provided an important component in the inflammatory process, revealing a key mechanisms underlying the induction of the central pro-inflammatory cytokine IL-1beta as well as IL-18 and a type of inflammatory cell death called pyroptosis. NLRP3 therefore emerged as a compelling therapeutic target for several inflammatory diseases, ranging from gout to osteoarthritis and even neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. We have developed highly specific inhibitors of NLRP3 which are have tremendous promise as a whole new class of drugs to treat inflammatory diseases.
NLRP3 was also strongly implicated in metabolic diseases such as atherosclerosis and NASH. Work on NLRP3, IL-1beta and metabolism formed part of the renaissance of interest in immunometabolism, which in this context means intracellular metabolic changes occurring in immunity that are governing for immune and inflammatory effector mechanisms. Metabolic changes triggered by innate immune receptors have become a particular focus for researchers interested in immunity and inflammation. This area has direct relevance to inflammatory diseases such as rheumatoid arthritis since the rheumatoid joint is known to undergo a range of metabolic alterations and enzymes in glycolysis are well known autoantigens. Furthermore metabolites from the Krebs Cycle such as succinate have been found to be elevated in rheumatoid synovial fluid and act via the receptor SUCRN1 on macrophages to boost IL-1beta production. LPS-activated macrophages undergo metabolic reprogramming with a major increase in glycolysis, which is required for ATP production and also the generation of biosynthetic intermediates. Changes in the Krebs cycle also occur such that intermediates such as citrate are withdrawn for lipid biosynthesis. We have found a role for the Krebs cycle intermediate succinate in activated macrophages. Succinate induces HIF-1alpha and it’s target genes, which include that encoding IL-1beta, can act on the aforementioned succinate receptor SUCRN1 on cells (which can synergise with TLRs) also can be oxidised by Succinate Dehydrogenase which because of the high mitochondrial membrane potential leads to reverse electron transport (RET) via Complex I in the mitochondria. This drives ROS production with inflammatory consequences. Succinate might therefore act as important signal for inflammation. We have also found that inhibition of SDH leads to IL-10 production, indicating that this enzyme is a key arbiter of cytokine production. A second metabolite termed itaconate is derived from citrate and has profound anti-inflammatory effects acting via NRF2. These insights are providing a new view of metabolism in immunity and inflammation and might indicate new therapeutic approaches.
Nobel Lectures 2017
Date and time: December 7, 2017, 13.00
Location: Aula Medica, Nobels väg 6, Karolinska Institutet, Solna
Free admission from 11.30. Seats must be taken by 12.40
Streaming to Nobel Forum, Wallenbergsalen
Live broadcasting at www.nobelprize.org
Jeffrey C. Hall
Brandeis University, Waltham, USA
“The Little Flies: Multifaceted Basic Research Coming Out Better than Intended”
Brandeis University, Waltham, USA, Howard Hughes Medical Institute, USA
“The circadian clock, transcriptional feedback and the regulation of gene expression”
Michael W. Young
Rockefeller University, New York, USA
“Time travels: A 40 year journey from Drosophila’s clock mutants to human circadian disorders”
Press Conference on December 6th, at 14:00, Nobel Forum, Nobels väg 1
On December 6th, a Press Conference with this year’s Nobel Laureates will be held for media and press representatives only.
Space is limited and individual registration and press accreditions are mandatory.
Nobel Lectures on December 7th, at 1.00 p.m., Aula Medica, Nobels väg 6
The official Nobel Lectures held by this year’s Nobel Laureates in Physiology or Medicine are held on December 7th.
For the general public: No registration required. Limited seating accomodated according to the first come, first served basis. No large bags or camera equipment allowed in Aula Medica except in the media section. Live broadcasting available at http://www.nobelprize.org and live streaming to a nearby lecture hall.
For press: For access to press section, registration and press accreditation is required. Please use the link below to register.
- Large bags or camera equipment only allowed in the media section, follow instructions on registration page.
- Individual accreditations are mandatory for media representatives due to limited space in the media section.
- Seats must be taken no later than 12.15 p.m.
- Press badge needed for entrance to the Aula Medica Lecture hall on the 7th of December must be picked up at the Reception Desk, Nobel Forum, Nobels väg 1, between 11 a.m. and 12 p.m., December 7th or in connection with the press conference on December 6th. Valid press ID required for badge pick up.