INFLAMMASOME IN INTESTINAL INFLAMMATION AND CANCER. Laura Stronati ENEA - Roma

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1 INFLAMMASOME IN INTESTINAL INFLAMMATION AND CANCER Laura Stronati ENEA - Roma

2 Inflammasome: definition, components and activation

3 TLRs NODs RLRs CLRs PRRs LPS, Flagellin, DNA, RNA, etc) PAMPs DAMPs ATP, HMGB1, HSPs,S100s, IL- 1a, Cysteine protease 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 proinflammatory cytokines, such as IL-1beta and IL-18 that engage the innate immune defence.

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5 tyr-val-his-asp116/ala117

6 sensor NLRs and PYHIN families Bacillus antracis MDP adapto r Candida albicans Saccaromyces cerevisiae Listeria monocytogenes Staphylococcus aureus Inflammatory caspase Salmonella typhimurium Shigella flexneri Legionella pneumophila Pseudomonas aeruginosa Schroder & Tschopp, Cell 2010

7 INFLAMMASOME ASC Activated NLRP3 Caspase-1 IL-1beta IL-18 INFLAMMATION +(d)atp Strpwig et al, Nature 2012

8 PRO-IL1BETA SYNTHESIS IL1BETA ACTIVATION Lissner & Siegmund, 2011

9 THIOREDOXIN TXNIP 1. The complex of purinergic receptor P2X7/pannexin1 for creating hemichannels in the membrane 2. Lysosomal machine for crystals or other particulate 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 Schroder & Tschopp, Cell 2010 Strowig et al, Nature 2012

10 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 downregulate inflammasomes Subsets of T cells able to suppress inflammasomes

11 Inflammasomes and associated diseases

12 Elinav et al, Mucosal Immunol 2013

13 Inherited and acquired diseases associated to inflammasome activation Rheumatoid arthritis (RA) Type-2 diabetes

14 Inflammasomes and intestinal inflammation

15 Inflammasome controls a number of common intestinal microbial infections Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis Lara-Tejero et al, JEM 2006 absence of caspase-1 or components of the inflammasome leads to increased susceptibility to infection

16 Role of inflammasome in host defence against Citrobacter rodentium infection. Liu Z et al, J Biol Chem 2012 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.

17 Inflammasome and Inflammatory Bowel Disease Humans IL-1beta and IL-18 production are enhanced in inflamed mucosa of IBD patients Mahida YR et al. 1989; Pizzarro TT et al, 1999; Monteleone et al, 1999 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 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

18 Inflammasomes and cancer

19 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) 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 Inflammasome have pleiotropic and contrasting roles in multiple facets of oncogenesis: they positivelly affect cellautonomous death pathways and anticancer immunosurveillance, but they also stimulate autocrine or paracrine processes that favor carcinogenic inflammation, tumor growth, metastasis and angiogenesis

20 contrasting roles oif inflammasome during carcinogenesis 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. Zitvogel et al, Nat Immunol 2012

21 EX HOC SEQUITUR: 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

22 I NFIAM M AZIONE SHEMEMET (INFLAMMATION) una storia lunga