Ferrara, Maggio 2012

Dipartimento di Diagnostica per Immagini e Medicina di LaboratorioDepartment of Experimental and Diagnostic Medicine

Center of Excellence MIUR for theStudy of Inflammation (ICSI)Ferrara University Hospital

Ferrara, Italy

L’ inflammasoma: la CPU (Central Processing Unit) della risposta

infiammatoria

F. Di Virgilio

Sommario

1. Che cos’ è l’ inflammasoma2. A che serve?3. Conclusioni

From van de Veerdonk et al, 2011

Inflammasome subtypes

Jurg Tschopp1951-2011

Dept. of Biochemistry

University of Lausanne

First reported about the “Inflammasome”

at a Conference in Maui in 2001

From Schroeder and Tschopp, Cell 2010

How a danger signaltranslates into activationof inflammation

Ludwig Institute for Cancer ResearchEpalinges, Lausanne

October 22, 1988

Seminars of the Department of Immunology

“The P2Z receptor of mouse macrophages”

Francesco Di Virgilio

Host: Giampietro Corradin

From Schroeder and Tschopp, Cell 2010

How a danger signaltranslates into activationof inflammation

Basics of Inflammation

Inducers Sensors Mediators Targets

Inducers/Triggers

Viruses, bacteria, protozoa………Poisons, toxic, xenobiotics….Cancer…..Misfolded proteinsCell and Tissue stressors…(ischemia!!!)Metabolic dysfunctionTrauma………….

Septic inflammation

Sterile inflammation

Figura 13.3 - I recettori dell'immunità innata e dell'infiammazione.

Dal volume: Pontieri “Patologia Generale” Piccin Nuova Libraria S.p.A.

Sensors

Stranger versus Danger

Modified from From Heath and Carbone, Nature 425:460-461, 2003

PAMP PRR

DAMP

I - Sensing the pathogen

II - Sensing the damage

How is inflammation started?

Modified from Davis et al, 2011

Inflammasome activators

The Inflammasome:a IL-1β producing machinery

From Dinarello, 2005

Dinarello 2011

From Hill et al., 2003, Mol Interv 3:19-26

Caspases are well known for their involvement in apoptosis

Initiator caspases are activated by “recruitment platforms” such asthe Death-Inducing Signalling Complex (DISC) for caspase-8 or theapoptosome for caspase-9

The apoptosome

APAF-like proteins:

The NOD-Like Receptors (NLR)NOD1, NOD2, NLRPs, IPAF, NAIPs

Apoptotic proteases-activating factor: APAF

Why “inflammasome?

From Schroeder and Tschopp, Cell 2010

The inflammasomes

“trigger”

NLR: NOD-like receptors

NOD1NOD2NLRC3NLRC5NLRX1

NALPs (NLRPs)

IPAF (NLRC4)NAIP

CIITA

Associated withthe inflammasome

Nucleotide-oligomerization domain

Modified from Davis et al, 2011

The inflammasome

No evidence of direct ligand binding to theinflammasome

Might NLRP3 sense changes in the cellular milieu?

Modified from Davis et al, 2011

Models of activation of the inflammasome

ROS? Source?NADPHox?Mitochondria?

ATP/P2X7?

Cathepsin?

Mitochondria and inflammation

From Tschopp, 2011

Di Virgilio, TIPS 2007

The P2X7-inflammasomeaxis

Le inflammasomopatie

Conclusioni

L’ inflammasoma è un complesso proteico a localizzazionecitoplasmatica responsabile dell’ attivazione della caspasi-1,e della conseguente conversione della pro-IL-1β in IL-1β.

Il meccanismo di attivazione non è ancora ben conosciuto, però è chiaro che l’ inflammasoma risponde alla presenza diPAMPS e DAMPS nell’ ambiente extracellulare e nelcitoplasma.

Difetti nell’ attivazione/disattivazione dell’ inflammasomasono alla base di numerose malattie infiammatorie cronichecaratterizzate da ipersecrezione (locale o sistemica) di IL-1β.

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