CONTACT

Virginie PETRILLI
Chef d'équipe
virginie.petrilli@lyon.unicancer.fr
04 78 78 28 28

Cheney D - 6ème étage
Centre Léon Bérard

PETRILLI Virginie
Chef d'équipe, CR1 CNRS, HDR
virginie.petrilli(at)lyon.unicancer.fr
HACOT Sabine
GORRY Julie

Ingénieure d'étude

HUBER Anne-Laure

Chargée de recherche INSERM  

 Anne-Laure.Huber@lyon.unicancer.fr

NADJAR Julien

Ingénieur d'étude

 

Voir les objectifs et projets Voir les publications

Collaborations

Bénédicte Py CIRI U1111

Olivier Destaing IAB U1209 UMR5309

Pascale Bertrand CEA Fontenay-aux-Roses

Fabio Martinon UNIL Suisse


Financements

ATIP/AVENIR programme - Plan Cancer 2

Ligue de lutte contre le cancer, comité de l’Ain, comité du Rhône

Fondation ARC

logo FRM


Bourse Marie Sklodowska-Curie

My team is dedicated to study novel functions and regulations of the inflammasomes in diseases with a special emphasis on cancer.

Background:
Inflammation is a biological process mounted by the innate immune system and plays a crucial role in the defense against pathogens and in tissue repair. When dysregulated, inflammation is responsible for many pathological disorders such as diabetes, ageing-related disorders including cancer. The initiation of the inflammatory response relies on the sensing of the Pathogen- Associated Molecular Pattern (PAMP) or the Damage-Associated Molecular Pattern (DAMP) by Pattern Recognition Receptors (PRR). Inflammasomes are cytosolic multiprotein complexes that play prominent roles in innate immunity and inflammation. They control the activation of caspase-1 and, as a consequence, the processing of the pro-IL-1
b and pro-IL-18 into active IL-1b and IL-18. In addition, caspase-1 cleaves the Gasdermin-D protein to induce a cell death named pyroptosis. NLRP3 is one of the PRR that triggers inflammasome assembly. It senses a variety of PAMPs and has the unique ability to detect DAMPs released by damaged cells during stress conditions. Thus, NLRP3 integrates a large diversity of stress signals, which all culminate in the activation of caspase-1. Inflammasome dysregulation results in many pathologies ranging from autoinflammatory disorders to cancer. But still more work is needed to fully understand how the NLRP3 inflammasome is regulated and its contribution to cancer.

Recently, we demonstrated that :

- the activation of the NLRP1b inflammasome by the anthrax Lethal Toxin in the absence of ASC results in IL-1b production and pyroptosis despite the absence of caspase-1 autoprocessing.

- NLRP3 is dispensable for NLRP1b activation.

- caspase-1 autoprocessing is mandatory for its activation within the NLRP3-inflammasome.

- the presence of an active inflammasome within the mammary tumor microenvironment facilitates mammary tumour growth  by inhibiting NK cell recruitment and activity.

We also discovered inflammasome independent function for NLRP3:

NLRP3 is a co-factor of the ATM required for full pathway activation

NLRP3 loss protects the cell from DNA damage induced cell death

-  NLPR3 is down-regulated in Non Small Cell Lung Cancer

 The main questions we are currently addressing in my team are the following:

-       Is NLRP3 a barrier to tumorigenesis?

-       How do NLRP3 functions are regulated?

Project 1: to understand the role of NLRP3 in the DNA damage response and repair (investigators: V. Petrilli, A. Tissier, A.L. Huber, S. Hacot, Gérossier L., D. Burlet)

Project 2: to determine at the molecular level how circadian clock regulate NLRP3 functions (investigators A.L. Huber, V. Petrilli)

Project 3: to develop novel tools to study inflammasome activation (investigators: J. Nadjar, V. Petrilli)

BACKGROUND

PUBLICATIONS

Guey B., Bodnar-Wachtel M., Drouillard A., Eberhardt A., Pratviel M., Goutagny N., Bendriss-Vermare N., Puisieux I., Caux C, Walzer T. and Petrilli V. Inflammasome deletion promotes anti-tumor NK cell function in an IL-1/IL-18 independent way in murine invasive breast cancer. Front. Oncol. 2020.  https://doi.org/10.3389/fonc.2020.01683.

Bodnar-Wachtel M.*, Huber A.L.*,  Gorry J., Hacot S., Gérossier L., Guey B., Goutagny N., Bartosch B., Balot E., Ghiringhelli F., Py B., Couté Y., Ballesta A., Lantuejoul S., Hall J. and Petrilli V. NLRP3 controls ATM activation in response to DNA damage. 2020. BioRXiv. DOI: 10.1101/2020.05.12.087015

Bonnin M, Fares N, Testoni B, Estornes Y, Weber K, Vanbervliet B, Lefrançois L, Garcia A, Kfoury A, Pez F, Coste I, Saintigny P, Viari A, Lang K, Guey B, Petrilli V, Hervieu V, Bancel B, Bartosch B, Durantel D, Renno T, Merle P, Lebecque S. Toll-like receptor 3 downregulation is an escape mechanism from apoptosis during hepatocarcinogenesis J Hepatol. 2019 Oct;71(4):763-772. doi: 10.1016/j.jhep.2019.05.031. Erratum in: J Hepatol. 2019 Nov 25 ;PMID:31220470.

Guey B, Bodnar M, Manié SN, Tardivel A and Petrilli V. Caspase-1 autoproteolysis is differentially required for NLRP1b and NLRP3 inflammasome function. Proc Natl Acad Sci U S A. published ahead of print November 17, 2014, doi:10.1073/pnas.1415756111.

Huber AL, Lebeau J, Guillaumot P,  Petrilli V, Malek M,  Chilloux J, Fauvet F , Payen L, Kfoury A, Renno T, Chevet E and Manié SN. p58(IPK)-mediated attenuation of the pro-apoptotic PERK-CHOP pathway allows malignant progression upon low glucose. Mol Cell. 2013 Mar 28;49(6):1049-59.

Erener S, Petrilli V, Kassner I, Minotti R, Castillo R, Santoro R., Hassa PO, Tschopp J and Hottiger MO. Inflammasome Activated Caspase 7 Cleaves PARP1 to Enhance NF-κB Dependent Transcription. Mol Cell. (2012) Apr 27;46(2):200-11.

Sharp FA, Ruane D, Claass B, Creagh E, Harris J, Malyala P, Singh M, O'Hagan DT, Pétrilli V, Tschopp J, O'Neill LA, Lavelle EC. Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome. Proc Natl Acad Sci U S A. (2009) Jan 20;106(3):870-5.

Gasse P, Riteau N, Charron S, Girre S, Fick L, Pétrilli V, Tschopp J, Lagente V, Quesniaux VF, Ryffel B, Couillin I. Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis. Am J Respir Crit Care Med. (2009) May 15;179(10):903-13.

Kool M., Pétrilli V., De Smedt T., Rolaz A., Hammad H., van Nimwegen M., Bergen I., Castillo R., Lambrecht B.N., Tschopp J. Alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J. Immunol. (2008) sept 15 ;181(6):3755-9.

Muruve D.A.*, Pétrilli V.*, Zaiss A.K., White L.R., Clark S.A., Ross P.J., Parks R.J., and Tschopp J. Recognition of cytosolic microbial and host DNA by the inflammasome triggers an innate immune response. Nature (2008) Mar 6;452(7183):103-7. * contributed equally to the work.

Dostert C., Pétrilli V., Van Bruggen R., Steele C., Mossman B.T. and Tschopp J. The Nalp3 inflammasome senses asbestos and silica and initiates innate immune responses. Science (2008) May 2;320(5876):674-7.

Pétrilli V., Papin S., Dostert C., Mayor A., and Tschopp J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. (2007) Sep;14(9):1583-9.

Reviews & Books 

Petrilli V.The multifaceted roles of inflammasome proteins in cancer. Current Opinion in Oncology. 2017. DOI: 10.1097/CCO.0000000000000346.

 

Guey B and Petrilli V. Assessing caspase-1 activation. Methods Mol Biol. NLR proteins, Springer.2016;1417:197-206. doi: 10.1007/978-1-4939-3566-6_13.


Bodnar M and Petrilli V. New insight in caspase-11 functions in noncanonical inflammasome signalling. Inflammasome (2014). DOI: 10.2478/infl-2014-0001.degruyter.com.

Pétrilli V., Dostert C., Muruve D.A. and Tschopp J. The inflammasome: a danger sensing complex triggering innate immunity. Curr Opin Immunol. (2007) Dec;19(6):615-22

Progress in Inflammation Research, “The inflammasomes”, editors Couillin/Pétrilli/Martinon. 2011. Springer Birkhäuser Basel AG. ISBN 978-3-0348-0147-8

Material and reagent info

Communauté Innate Sensors

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