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Vascular Biology : Endothelial cells, Inflammation and Cancer

Jean-Philippe Girard

Group Leader

Our team is among the world leaders for the characterization of high endothelial venules (HEVs), portals of entry for lymphocytes into lymphoid organs, inflamed and tumor tissues (~ 25 years expertise), and for the study of IL-33, a nuclear cytokine from the IL-1 family that we discovered in 2003, which plays crucial roles in innate immunity and allergic inflammation.

 

eq_girard.jpgWe demonstrated that dendritic cells, which are well known for their role as antigen-presenting cells, play an unexpected and important role in the maintenance of HEV blood vessels in lymph nodes (Nature 2011).

In addition, we discovered the frequent presence of HEVs in human solid tumors, and their association with cytotoxic lymphocyte infiltration and favourable clinical outcome in breast cancer.

 

Our study introduced a novel concept in cancer biology “Blood vessels in human tumors are not all the same and some types of blood vessels found in the tumor microenvironment (i. e. HEVs) can contribute to tumor suppression rather than tumor growth” (Cancer Res 2011).

A better understanding of HEVs at the molecular level, which is one of the major objectives of our team, may have an important impact for cancer therapy.

Our team showed that IL-33 is a chromatin-associated cytokine (PNAS 2007, 543 citations) that function as an alarm signal (alarmin) released upon cellular damage (PNAS 2009, 373 citations>).

We demonstrated that inflammatory proteases can generate truncated forms of IL-33 that are 30-fold more potent than the full length protein for activation of group 2 innate lymphoid cells (PNAS 2012, 193 citations, PNAS 2014).

 

Recently, we discovered that full length IL-33 functions as a protease sensor that detects proteolytic activities associated with a large variety of environmental allergens (Nature Immunology 2018). An important objective of our team is to further characterize IL-33 regulation and mechanisms of action in vivo, through the use of multidisciplinary approaches.

 

Main publications

  • Cayrol C et al. (2018) Environmental allergens induce allergic inflammation through proteolytic maturation of IL-33. Nature Immunology 19: 375-385
  • Liew FY, Girard JP and Turnquist HR (2016) Interleukin-33 in health and disease. Nature Rev Immunol 16: 676–689
  • Girard JP, Moussion C and Forster R. (2012) HEVs, Lymphatics and homeostatic immune cell trafficking in lymph nodes. Nature Rev Immunol 12: 762-773
  • Martinet L et al. (2011) Human solid tumors contain high endothelial venules (HEV): association with T and B lymphocyte infiltration and favourable prognosis in breast cancer. Cancer Res 71: 5678-5687
  • Moussion C and Girard JP. (2011) Dendritic cells control lymphocyte entry to lymph nodes via high endothelial venules. Nature 479: 542-546

 

image_girard_science.jpgHigh endothelial cells from HEVs (green) are characterized by a plump morphology and express high levels of the nuclear cytokine IL-33 (red).

 

Scientists

Jean-Philippe Girard

INSERM Research director

Emma Lefrançais

CNRS Research associate in immunology

Nathalie Ortéga

Associate Professor in Molecular Biology - University of Toulouse

Raoul Mazars

Associate Professor in Cellular Biology - University of Toulouse

Research Assistants

Elisabeth Bellard

CNRS Engineer

Pascale Mercier

CNRS Engineer

Stéphane Roga

PhD Students

Juliette Coudert

Fellow of the Ministry of Higher Education & Research

Robin Laffont

Fellow of the Ministry of Higher Education & Research

Pauline Schmitt

Fellow of the Ministry of Higher Education & Research

Lucas Blanchard

Fellow of the 'Fondation pour la recherche médicale'

Main publications on HEV Topic

  • Martinet L*, Garrido I*, Filleron T, Le Guellec S,  Bellard E, Fournie JJ, Rochaix P and Girard JP. Human solid tumors contain high endothelial venules (HEV): association with T and B lymphocyte infiltration and favourable prognosis in breast cancer. Cancer Res, 2011, 71:5678-5687 (Press release from CNRS/INSERM; This article has been highlighted in Cancer Res 71:5601-5; 167 citations in Web of Science, WOS)

We went against the dogma that ‘blood vessels facilitate tumor growth’ and introduced a novel concept in cancer biology ‘Blood vessels in human tumors are not all the same and some types of blood vessels (i. e. tumor-associated HEVs) may contribute to the fight against cancer’

 

  • Moussion C and Girard JP. Dendritic cells control lymphocyte entry to lymph nodes via high endothelial venules. Nature, 2011, 479:542-546 (Press release from CNRS/INSERM; Faculty of 1000-Biology, Recommended; 133 citations in WOS)

We showed that dendritic cells, which are well known for their role as antigen-presenting cells, play an unexpected and important role in the maintenance of HEV blood vessels in adult lymphoid tissues

 

  • Martinet L, Le Guellec S, Filleron T, Lamant L, Meyer N, Rochaix P, Garrido I and Girard JP. High endothelial venules (HEVs) in human melanoma lesions: major gateways for tumor-infiltrating lymphocytes. OncoImmunology, 2012, 1:829-839 (59 citations in WOS)

We found that high densities of tumor-associated HEVs are correlated with high levels of lymphocyte infiltration and good clinical characteristics in human melanomas

 

  • Martinet L, Filleron T, Le Guellec S,  Rochaix P, Garrido I and Girard JP. HEV Blood Vessels for Tumor-Infiltrating Lymphocytes are Associated with Lymphotoxin b-Producing Dendritic Cells in Human Breast Cancer. J Immunol, 2013, 191:2001-2008 (This article has been highlighted in J Immunol 191:1508; 45 citations in WOS)

We found that the density of tumor-associated HEVs within human breast tumors is correlated to the density of lymphotoxin b-producing dendritic cells

 

  • Lafouresse F, Bellard E, Laurent C, Moussion C, Fournié JJ, Ysebaert L and Girard JP. L-selectin controls trafficking of chronic lymphocytic leukemia cells in lymph node high endothelial venules in vivo. Blood, 2015, 126:1336-1345 (Press release from CNRS/INSERM; This article has been selected by the Editors for the cover of the journal and a research highlight in “Inside Blood” 2015, 126:1267-1268)

We used intravital microscopy in mouse to study the in vivo trafficking in HEVs of human leukemic cells from chronic lymphocytic leukemia patients 

Reviews on HEV Topic

  • Girard JP*, Moussion C and Forster R.  HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nature Rev Immunol, 2012, 12:762-773 (* Corresponding author; 207 citations in WOS, Top 1%)

We were invited by Nature Rev Immunol Chief Editor to write a comprehensive review on the role of HEV blood vessels in lymphocyte migration to lymph nodes

 

  • Veerman K, Lafouresse F and Girard JP. Tumor High Endothelial Venules and Lymphocyte Trafficking. In ‘Molecular Mechanisms of Angiogenesis’, JJ. Feige, G Pagès, F Soncin, ed. (Springer), 2014, 339-352.

We were invited to write a comprehensive review on the role of HEV blood vessels in cancer

Main publications on IL-33 Topic

  • Carriere V#, Roussel L#, Ortega N, Lacorre DA, Americh L, Aguilar L, Bouche G and Girard JP. Interleukin-33, the IL-1-like ligand for ST2 receptor, is a chromatin associated nuclear factor in vivo. Proc. Natl. Acad. Sci. USA, 2007, 104:282-287(#first co-autors; This article has been highlighted in Science Signalling 2007(390):pe31; 543 citations in WOS)

We showed that the IL-1-like cytokine IL-33 is a chromatin-associated cytokine, which is identical to NF-HEV, the nuclear factor that we cloned from purified HEV endothelial cells in 2003.

 

  • Moussion C#, Ortega N# and Girard JP. The IL1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo : a novel “alarmin” ? PLoS ONE, 2008, 3(10):e3331 (# co-first authors, 548 citations in WOS, Top 1%)

We reported that IL-33 is constitutively expressed in blood vessels and epithelial barrier tissues, and we proposed the concept that IL-33 may function as a novel alarmin (alarm signal) rather than as a classical cytokine (we were the first to propose this concept).

 

  • Cayrol C and Girard JP. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc. Natl. Acad. Sci. USA, 2009, 106:9021-9026. (This article has been highlighted in Immunity 2009, 31:5-7; 373 citations in WOS, Top 1%)

Contrary to the dogma in the field, we showed that IL-33 does not require maturation for biological activity and that cleavage by caspases results in IL-33 inactivation, rather than activation (We were the first to report these findings, which were later confirmed by 3 other teams).

 

  • Lefrançais E,  Roga S, Gautier V, Gonzalez-de-Peredo A, Monsarrat B, Girard JP* & Cayrol C*. IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. Proc. Natl. Acad. Sci. USA, 2012, 109:1673-1678 (* Co-senior authors; Press release from CNRS/INSERM, Faculty of 1000-Biology, Recommended; 196 citations in WOS, Top 1%)

We showed that processing of IL-33 by inflammatory proteases generate mature forms of the cytokine with highly increased biological activity

 

  • Lefrançais E#, Duval A#, Mirey E, Roga S, Espinosa E, Cayrol C* and Girard JP*. Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells. Proc Natl Acad Sci U S A, 2014, 111:15502-7. (# co-first authors,* Co-senior authors; Press release from CNRS/INSERM; This article has been highlighted in JACI, 2015, 135:1-2; 90 citations in WOS).

We discovered that cleavage within the central domain of IL-33 generates truncated forms that are 30-fold more potent than the native protein for activation of ILC2s, the major targets of IL-33 in vivo.

 

  • Cayrol C*#, Duval A#, Schmitt P, Roga S, Camus M, Stella A, Burlet-Schiltz O, Gonzalez-de-Peredo A and Girard JP*. Environmental allergens induce allergic inflammation through proteolytic maturation of IL-33. Nature Immunology, 2018, 19:375-385 (# Co-first authors; *Co-corresponding authors; National press release from INSERM/CNRS; This article has been highlighted in Nature Immunol. 2018 News and Views 19:318-320 and Nature Rev Immunol 2018 May issue; Recommended in F1000Prime).

We discovered that IL-33 functions as an allergen protease sensor that detects proteolytic activities associated with various clinically relevant aeroallergens and initiates allergic inflammation shortly after allergen exposure
 

Reviews on IL-33 Topic

  • Liew F. Y., Girard JP and Turnquist H. R. Interleukin-33 in health and disease. Nature Rev Immunol, 2016, 16(11), 676–689.

We were invited to write a state of the art review on IL-33 protein and its roles in immunity and allergic inflammation.

 

  • Cayrol C and Girard JP. IL-33: an alarmin cytokine with critical roles in innate immunity, inflammation and allergy. Curr Opin Immunol, 2014, 31:31-37 (97 citations in WOS, Top 1%, Hot Paper)

We were invited to write a state of the art review on IL-33 mode of action, regulation and functions in health and disease.

 

  • Cayrol C and Girard JP. Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family. Immunological Reviews, 2018; 281: 154-168.
    We were invited to write a state of the art review on IL-33 mode of action and regulation
  •  

  • Publications

  • Download a complete list of the papers of the team from 1992 to 2016
  • Patents

  • Title NOVEL SUPERACTIVE IL-33 FRAGMENTS, AND USES THEREOF
  • Publication N° : WO/2012/113927 
  • Publication Date : 30.08.2012 
  • International Application No : PCT/EP2012/053199 
  • Applicants : CNRS 
  • Inventors : GIRARD, Jean-Philippe;CAYROL-GIRARD, Corinne; LEFRANCAIS, Emma
  • Patent Summary
  • More informations on licensing opportunity

Grants and Fellowships

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Jean-Philippe Girard, recipient of the Jean-Paul Binet Prize from “Fondation pour la Recherche Médicale”

Dr. Jean-Philippe GIRARD, received the Jean-Paul Binet Prize 2016 on December 5th, at the “Fondation pour la Recherche Médicale” in Paris.

This Prize rewards researchers who have made important advances in the understanding of the cardiovascular system. Jean-Philippe Girard received the prize for his work on HEV blood vessels and their role in inflammation and cancer.

His intervention at the "Fondation pour la recherche médicale" (in french)

 

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Jean-Philippe GIRARD, Director of IPBS, winner of the prestigious Prize in Cancerology “GALLET et BRETON” from the National Academy of Medecine

Dr. Jean-Philippe GIRARD received the prize “GALLET et BRETON” on December 17th 2013, at the National Academy of Medecine in Paris. This prestigious Prize in Cancerology rewards researchers who have made important advances in cancer research or cancer therapy. Jean-Philippe Girard received the prize for his work on HEV blood vessels and their role in cancer. More Informations...

Jean-Philippe GIRARD, Silver Medal of the CNRS

The CNRS Silver Medal honors researchers who are only at the beginning of their rise to fame, but who are already recognized nationally and internationally for the originality, quality, and importance of their work.

Jean-Philippe GIRARD, Director of IPBS, received this prestigious award for his work on the role of blood vessels in inflammation and cancer.

 

More Informations...

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Dr. Jean-Philippe GIRARD, winner of the prestigious prize “Grand Prix René Turpin de Cancérologie” from the National Academy of Sciences

On October 16th 2012, Dr. Jean-Philippe GIRARD received the prestigious Prize in Cancerology, delivered every two years by the National Academy of Sciences and the ‘Institut de France’, for his work on HEV blood vessels and their role in cancer.

More info on the work of Jean-Philippe Girard on HEV blood vessels

Link with the two press releases (Nature 2011 and Cancer Res 2011)

Pr Jean-François BACH, from the National Academy of Sciences, discuss the originality and the importance of the work of Jean-Philippe Girard for cancer research and treatment during the prize ceremony at the Institut de France in Paris. 

See the video (in french)

Dr. Jean-Philippe GIRARD received the first "Stars of the Health (Étoiles de la Santé) Cancer Research Prize 2012

On 27 September 2012, Dr. Jean-Philippe GIRARD, Director of IPBS, received the first "Stars of the Health (Étoiles de la Santé) Cancer Research Prize" at the ’Cité de l’Espace’ in Toulouse, France.

The "Stars of the Health Prizes" were delivered for the first time this year by Foundation Oréade-Prévifrance. This event aimed at celebrating clinical, therapeutic and scientific research actors as well as start-up, pharmaceutical companies and associations working in the field of "Health and Medicine" in the south-west of France.

Five awards were delivered including "The Cancer Research Award" which rewards teams involved in fundamental or clinical research in the field of prevention and treatment of cancer. This award was given to Dr Jean-Philippe Girard and his team for their work on HEV blood vessels in human cancer.

Dr Girard receives the “"Stars of the Health Cancer Research Prize 2012"” at the ’Cité de l’Espace’ in Toulouse on September 27th (in French)

http://www.previfrance.fr/les-etoil...

http://www.ladepeche.fr/article/201...

 

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The “Ruban Rose Avenir 2011” Prize awarded to Dr Jean-Philippe GIRARD

Dr Jean-Philippe Girard, Director of IPBS and Head of the team “Vascular biology : endothelial cells, inflammation and cancer” is the recipient of the “Ruban Rose Avenir 2011 Prize”.

The“Ruban Rose Prizes” are awarded each year since 2004 to researchers who have made important contributions in breast cancer research.

More informations...

Fanny Lafouresse received in 2015 a travel grant and the best oral presentation award (Biolegend) at the World Immune Regulation meeting IX (Davos, Switzerland)

 

Anaïs Duval received in 2014 the best poster prize from ’Nature Immunology’ at the EMBO conference in Innate Lymphoid Cells (Pasteur, Paris).


Fanny Lafouresse received the best oral communication prize 2013 from the SILLC association.

 

Christine Moussion received the Paul Sabatier Prize 2012 from the "Académie des Sciences, Inscriptions et Belles Lettres de Toulouse"

The European Cytokine Society Prize 2012 (Junior Publication Initiative) was awarded to Emma Lefrançais.


Ludovic Martinet and Emma Lefrançais received the best poster and oral communication prize 2011 from the "Société Française d’Angiogenèse"


Emma Lefrançais received the best poster prize 2011 from the Cold Spring Harbor Asia Conference ’Infection and Immunity’