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Fields of research


Appropriate inflammatory response efficiently participates in the organismal protection against infections and mediates tissue repair following injuries. Adversely chronic or excessive inflammation is detrimental upon sepsis and fuels pathogenesis of a large set of highly prevalent multifactorial conditions including Alzheimer’s disease, type 2 diabetes, atherosclerosis and cancer. Our objective is to decipher the molecular mechanisms controlling inflammation, in order to propose innovative therapeutics against these diseases as well as to improve their diagnosis and prevention.

At the molecular level, inflammation is triggered by a battery of receptors recognizing molecular structures specific to microorganisms (PAMP, pathogen-associated molecular pattern) or signals resulting from cellular damage and metabolic stress (DAMP, damage-associated molecular pattern). These receptors are highly diverse in their specificities, subcellular localizations and downstream signaling pathways, and constitute a network able to trigger an appropriate response to a large variety of insults.

Our research focuses on NLRP3, a cytosolic receptor involved in the response to all kinds of pathogens (virus, bacteria, fungi and parasites) but also in deleterious inflammation associated to numerous human pathologies including Gout arthritis, Alzheimer’s disease, type 2 diabetes and atherosclerosis. Low-grade NLRP3-mediated inflammation participates in age-related functional decline. In addition, mutations in NLRP3 gene cause hereditary autoinflammatory syndrome. Therefore, NLRP3 is particularly relevant in regards to multiple highly prevalent conditions.

Upon activation, NLRP3 assembles an oligomeric complex named inflammasome, serving as an activation platform for caspase-1. Caspase-1 protease then controls maturation and secretion of key proinflammatory cytokines, and can trigger a proinflammatory form of cell death named pyroptosis.

NLRP3 does not directly bind its diverse activators and we still know very little about the molecular mechanism of NLRP3 activation. Using a pharmacological approach, we recently discovered that inflammasome assembly is regulated by NLRP3 post-translational modifications. Our research combines biochemistry and cell biology approaches with analysis of transgenic mouse models and patients studies in order to get a better understanding of NLRP3 activation mechanism.




Cochlin is an extracellular matrix protein expressed in restricted tissues including secondary lymphoid organs suggesting a possible function of cochlin in immunity.

We described that Cochlin is produced by stromal follicular dendritic cells that secrete cochlin in the lumen of extracellular matrix structures of the spleen and lymph nodes. This structures are named conduits and constitute a collagen-filled tubular network opened on the efferent bloodstream. Cochlin accumulates in the conduits lumen where it is probably trapped through its interaction with collagen.

Upon inflammation, Cochlin is cleaved by the inducible metalloprotease Aggrecanase-1, releasing Cochlin LCCL N-terminal domain in the bloodstream. LCCL domain is conserved in Limulus Factor C, a key antibacterial factor released in the hemolymph upon bacterial infection, suggesting a similar role of Cochlin in antibacterial immunity in Mammals. Indeed, following intranasal infection with Gram-positive Pseudomonas aeruginosa or Gram-negative Staphylococcus aureus, Cochlin LCCL is released in the bloodstream and accumulates at the site of infection. Coch-/- mice show defect in controlling growth of P. aeruginosa and S. aureus in the lung, and their spread to other organs. Coch-/- mice show reduced survival to infection. Secretion of proinflammatory cytokines and chemokines, as well as macrophages and neutrophils recruitment are reduced in the lung, i.e. the infection site, of Coch-/- mice.

Our work evidences a physiologic function of Cochlin as a pro-inflammatory blood circulating factor. In addition, our study identifies a new function for the conduits acting as a reservoir for ready-to-be-released immune regulators. Finally, our results suggest an unexpected role of follicular dendritic cells in regulating innate immunity while they were mostly described as modulators of humoral immunity promoting activation and maturation of B cells.


Immune response to sepsis

Sepsis, defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, represents a major healthcare challenge recently acknowledged as a worldwide health priority by the WHO because of its high incidence and mortality. Our research has largely participated in the better description of the pathophysiology of the deregulated immune response induced after sepsis by demonstrating that the initial pro-inflammatory response leading to organ failure and shock is compensated by the delayed development of immune dysfunctions. This sepsis-induced immunosuppression is evidenced by patients’ frequent inability to eradicate their primary infection and their propensity to acquire new secondary infections.

We aim to study mechanisms leading to sepsis-induced immune alterations in a translational research approach. The objective is to identify innovative therapeutic strategies targeting host immune response in sepsis and companion biomarkers in a personalized medicine approach. The role of several pathophysiological pathways will be explored.

More specifically, accumulative evidence from the literature describe the role of NLRP3 pathway activation in the initial pro-inflammatory response to LPS injection sepsis model, but few data are available during sepsis-induced immunosuppression let alone in clinical samples from patients. We develop a translational research program focused on the role of NLRP3 inflammasome in the immune response to sepsis. We investigate whether NLRP3 inflammasome activation is central to the pathophysiology of sepsis with a dual role (i) through its hyper-activation during the initial phase of the disease leading to cytokine storm and organ failure and (ii) through its down-regulation/inhibition during sepsis-induced immunosuppression leading to immune dysfunctions, endotoxin tolerance and increased risk of secondary infections. 


We thank our current and past funders:

IDEXLYON (2019-2021) : IDEX ANR-16-IDEX-0005 (in collaboration with Pr D Zamboni, University of Sao Paulo, Brazil)
Fondation Finovi (2019-2021) : in collaboration with Dr V. Petrilli, CRCL, Lyon
ERC — Consolidator grant (2014-2022) : ERC-2013-CoG_616986
ANR — Young Investigator program (2013-2017) : ANR-13-JSV3-0002-01
ANR : ANR-20-CE92-0024-01 (in collaboration with Pr A Nystrom, University of Freiburg, Pr O Schilling, University of Freiburg, Pr F Venet, University of Lyon)

ANR : ANR-22 (in collaboration with Dr V. Petrilli, CRCL, Lyon, Dr L. Boyer, C3M, Nice and Dr R. Ricci, IGBMC, Strasbourg)


This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no ERC-2013-CoG_616986.

Benedicte PY

CIRI, Cervi/INSERM Tower, 6th floor
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