SPEAKER
Prof Luke O’NEILL
Chair of Biochemistry at Trinity College Dublin
where he leads the Inflammation Research
Group,
Co-founder of 2 Spin-out companies -
Opsona Therapeutics and Inflazome,
Dublin, Ireland
HOST:
Department of Infection and Immunity
RESPONSIBLE LIH SCIENTIST:
Prof Dirk Brenner (dirk.brenner@lih.lu)
www.lih.lu
Supported by:
|
FRONTIERS IN INFLAMMATION RESEARCH: FROM NLRP3 TO
METABOLIC REPROGRAMMING
ABSTRACT
|
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that intermediates such as citrate are withdrawn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.
|
* Opposite Luxembourg Institute of Health, House of BioHealth, 29, rue Henri Koch L-4354 Esch/Alzette
|
|