Inflammasoma e malattie

Transcription

1 Inflammasoma e malattie Ferrara, Novembre 2017

2 The rediscovery of inflammation Body Defense Dummy arm Smart arm Inflammation Innate Immunity Adaptive Immunity tumor, calor, dolor, rubor Very smart Control Unit Inflammation Effector Branches Innate Immunity Adaptive Immunity

3 L infiammazione è lucrosa Global anti-inflammatory drug market 32.3 miliardi $ nel nel nel 2017 (proiezione) Global analgesic market 34.6 miliardi $ nel 2015 Global antibiotic market 40.3 miliardi $ nel 2015 Global antidepressant drug market 11.9 miliardi $ in 2011 Global anticancer drug market 75 miliardi $ nel 2013

4 «..a caspase-activating complex..» «comprising caspase-1, caspase-5, Pycard/ASC and NALP1»

5 Inflammasome(s): the CPU that integrates PAMP and DAMP signals PAMP? CPU Inflammasome?? RAGE P2X7 DAMP DAMP

6 How is inflammation started? Stranger versus Danger DAMP PAMP PRR II - Sensing the damage I - Sensing the pathogen Modified from From Heath and Carbone, Nature 425: , 2003

7 Perché l inflammasoma? Struttura/organello intracellulare che catalizza la maturazione (ed il rilascio?) dell IL-1b matura

8 The Inflammasome a IL-1b producing machinery Caspase-1 activating platform NEK7

9 Why inflammasome? Caspases are well known for their involvement in apoptosis Initiator caspases are activated by recruitment platforms such as the Death-Inducing Signalling Complex (DISC) for caspase-8 or the apoptosome for caspase-9 Apoptotic proteases-activating factor: APAF APAF-like proteins: The NOD-Like Receptors (NLR) NOD1, NOD2, NALPs, IPAF, NAIPs The apoptosome From Hill et al., 2003, Mol Interv 3:19-26

10 Basic structure of the inflammasome Sensor protein Scaffold protein NEK7 Effector protein Adaptor/regulatory protein Caspase-11 inflammasome Inflammasomi atipici From Davis et al., Ann Rev Immunol 2011

11 Caspase-11 triggers pyroptosys and IL-1 release, but is not coupled to a NLR protein

12 P2X7-activated NLRP2-inflammasome in astrocytes Di Virgilio, Pharmacol Rev 2013

13 Pathogen selectivity NLRP1 Bacillus anthracis lethal toxin NLRP3 LPS, muramyl dipeptide, peptidoglycan, bacterial and viral RNA, viral DNA, maitotoxin, ATP, MSU, amyloid beta, cholesterol, asbestos, silica.. S. aureus, L. monocytogenes, Klebsiella pneumoniae, N. gonorrheae E. coli, Candida albicans.. NLRP6 L. monocitogenes, S. tiphimurium, E. coli NLRP7 lipopeptides NLRP12 Yersinia pestis NLRC4 bacterial flagellin Salmonella, Shigella, Pseudomonas, Legionella AIM2 Francisella tularensis, M. tuberculosis

14 All roads lead to Rome

15 All roads lead to Rome (cntd)

16 I diversi sottotipi di inflammasomi possono essere pensati come diverse vie di attivazione della caspasi-1 in risposta a diversi stimoli pro-inflammatori di origine endogena o esogena

17 Any relevance to human diseases? Autoinflammatory diseases Intrinsic and extrinsic inflammasomopathies pyrin Familial Mediterranean Fever (FMF) Cold-induced autoinflammatory syndrome 1 cryopyrin CIAS1-associated periodic syndrome(s) CAPS (cryopyrinopathies) Familial cold autoinflammatory syndrome (FCAS) Muckle-Wells syndrome Chronic infantile neurological cutaneous and articular syndrome (CINCA)

18 Inflammasomopatie intrinseche: mutazioni a carico di NLRP3 Inflammasomopatie estrinseche: mutazioni/disfunzioni di fattori regolatori l inflammasoma NLRP3

19 Familial cold autoinflammatory syndrome (FCAS) Muckle-Wells syndrome Chronic infantile neurological cutaneous and articular syndrome (CINCA) Familial Mediterranean Fever (FMF)

20 CAPS

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22 FMF

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24 Exitus: spesso per insufficenza renale cronica da amiloidosi renale

25 Expanding functions of the inflammasome(s) in clinical medicine

26 Intrinsinc and extrinsic inflammasomopathies

27 Se l inflammasoma è il processore intracellulare dell IL-1, allora per individuare le inflammasomopatie seguiamo l IL-1

28 Different ways to antagonize IL-1b

29 Se l inflammasoma è il processore intracellulare dell IL-1, allora per individuare le inflammasomopatie seguiamo l IL-1

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31 Autoimmunity and autoinflammation

32 Malattie autoinfiammatorie ed autoimmunitarie: sono diverse?

33 Expanding functions of the inflammasome(s) Cryopyrinopathies Familial Mediterranean Fever Gout and pseudogout Adjuvants Misfolded proteins (amyloid b and serum amyloid A) Atheroscleorosis Metabolic diseases (Type II diabetes) Rethinopathies (diabetic retinopathy, ischemia-dependent injury of retinal ganglion cells, Age-related macular degeneration) Cardiac diseases (hypoxia-reoxygenation injury, post-infarct cardiac remodeling) Cancer (a role in colitis-induced cancer? Immunogenic cell death/immunochemotherapy? Cancer cell proliferation?)

34 NLRP3 activation by diabetes-related DAMPs IAPP = islet amyloid poly-peptide

35 Pathogenesis of pancreatic damage in T2DM Glucotoxicity IAPP toxicity IL-1-dependent toxicity

36 NLRP3 signalling in liver pathology

37 The liver as both a target and a source of DAMPs

38 Cardiac remodeling Cardiac remodeling can be described as a physiologic and pathologic condition that may occur after myocardial infarction (MI), pressure overload (aortic stenosis, hypertension), inflammatory heart muscle disease (myocarditis), idiopathic dilated cardiomyopathy or volume overload (valvular regurgitation).

39 DAMPs-mediated extension of post-mi damage Inflammatory cell recruitment Inflammation-dependent Myocardial damage Necrotic tissue

40 Mechanism of inflammasome activation following MI

41 Inflammatory pathways as potential targets for atherosclerosis therapies

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43 Dimethyldioctadecylammonium/monophosphoryl lipid-a (DDA/MPL)

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46 PAMPs DAMPs??