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)