INFLAMMASOME IN INTESTINAL INFLAMMATION AND CANCER … · 2014. 3. 28. · Inflammasome controls a...
Transcript of INFLAMMASOME IN INTESTINAL INFLAMMATION AND CANCER … · 2014. 3. 28. · Inflammasome controls a...
INFLAMMASOME IN INTESTINAL
INFLAMMATION AND CANCER
Laura Stronati
ENEA - Roma
Inflammasome: definition, components
and activation
Inflammasomes are a group of
protein complexes that assemble
upon recognition of a diverse set
of noxious stimuli and are now
considered the cornerstone of
the intracellular surveillance
system.
Inflammasomes trigger the
activation of caspase-1
promoting the secretion of pro-
inflammatory cytokines, such as
IL-1beta and IL-18 that engage
the innate immune defence.
Cysteine
protease
PRRs
TLRs
NODs
RLRs
CLRs
PAMPs
DAMPs
LPS, Flagellin,
DNA, RNA, etc)
ATP, HMGB1,
HSPs,S100s, IL-
1a,…
tyr-val-his-asp116/ala117
Schroder & Tschopp, Cell 2010
NLRs and PYHIN families
sensor
adapto
r
Inflammatory
caspase
Bacillus antracis
MDP
Salmonella typhimurium
Shigella flexneri
Legionella pneumophila
Pseudomonas aeruginosa
Candida albicans
Saccaromyces cerevisiae
Listeria monocytogenes
Staphylococcus aureus
Strpwig et al, Nature 2012
Activated NLRP3
ASC
Caspase-1
INFLAMMASOME
IL-1beta
IL-18
+(d)ATP
INFLAMMATION
Lissner & Siegmund, 2011 PRO-IL1BETA SYNTHESIS IL1BETA ACTIVATION
3. PAMPs (LPS, Flagellin, DNA,
RNA, etc) and DAMPs (HMGB1-
S100s-HSPs-IL1a,…)
interacting with PRRs (TLRs-
NODs-RLSs-CLRs) produce
ROS that activate TXN
1. The complex of purinergic
receptor P2X7/pannexin1 for
creating hemichannels in the
membrane
2. Lysosomal machine for
crystals or other particulate
THIOREDOXIN
TXNIP
Strowig et al, Nature 2012 Schroder & Tschopp, Cell 2010
Regulatory mechanisms of inflammasome activation
Lower expression of inflammasome sensors
Regulatory proteins: proteins that sequester
inflammasome components - inhibitors (viral
proteins, bacterial virulence factors)
Cellular processes (autophagy) able to down-
regulate inflammasomes
Subsets of T cells able to suppress inflammasomes
Inflammasomes and associated diseases
Elinav et al, Mucosal Immunol 2013
Rheumatoid arthritis (RA) Type-2 diabetes
Inherited and acquired diseases associated to
inflammasome activation
Inflammasomes and intestinal inflammation
absence of caspase-1 or components of the inflammasome leads to increased
susceptibility to infection
Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis Lara-Tejero et al, JEM 2006
Inflammasome controls a number of common intestinal microbial
infections
Production of IL-1β and IL-18 downstream of the Nlrp3 inflammasome plays a
critical role in host defense against enteric infections caused by C. rodentium.
Role of inflammasome in host defence against Citrobacter rodentium infection. Liu Z et al, J Biol Chem 2012
Inflammasome and Inflammatory Bowel Disease
Mahida YR et al. 1989; Pizzarro TT et al, 1999; Monteleone et al, 1999
IL-1beta and IL-18 production are enhanced in inflamed mucosa
of IBD patients
Humans
Mouse
Neutralization of IL-18 in mice with colitis reduces disease
severity
Kanai T et al 2003, Sivakumar PV et al, 2001, Ten Hove T et al, 2001
Variants of inflammasome genes have been associated with
susceptibility to CD
Villani AC et al, 2009, Schoultz I et al, 2009; Verma D et a,l 2008; Lewis
GJ et al, 2008
Inflammasomes and cancer
Inflammasome have pleiotropic and contrasting roles in
multiple facets of oncogenesis: they positivelly affect cell-
autonomous death pathways and anticancer
immunosurveillance, but they also stimulate autocrine or
paracrine processes that favor carcinogenic inflammation,
tumor growth, metastasis and angiogenesis
The link between chronic inflammation and carcinogenesis can
be explained by the production of DNA-damaging oxygen
radical species, pro-inflammatory mediators that promote cell
survival, enhance proliferation and angiogenesis and tissue
remodeling, resulting in a microenvironment conducive to
tumorigenesis
Many human cancers are etiologically linked to chronic
inflammatory processes: this is well documented in gastric
cancer, hepatic cancer and colo-rectal cancer (Grivennikov et al Cell
2010; Schafer &Werner, Nat Rev Mol Biol 2008)
contrasting roles oif inflammasome during carcinogenesis
Zitvogel et al, Nat Immunol 2012
At present, it is not possible to formulate an equivocal set
of recommendations to stimulate or inhibit inflammasomes
or their products in the context of cancer therapy.
Depending on the particular neoplasm and its stage,
inflammasome inhibition may be envisioned as a
therapeutic otpion or counterindicated.
Inflammasomes are believed to maintain the
homeostasis within the intestine
Excessive inflammasome activation within the
lamina propria contributes to severe intestinal
inflammation.
Inflammasomes have pleiotropic and contrasting
roles in carcinogenesis and anticancer immune
response
EX HOC SEQUITUR:
I NFI AM M AZI ONE
una storia lunga…SHEMEMET (INFLAMMATION)