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Vascular biology - Endothelial cells in Immunity, 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, 641 citations) that function as an alarm signal (alarmin) released upon cellular damage (PNAS 2009, 439 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, 288 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, 75 citations). 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

 

Jean-Philippe Girard joins the world's most influential researchers, according to the Web of Science Group's Highly Cited Researchers 2019 list

 

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

PhD Students

Lucas Blanchard

Fellow of the 'Fondation pour la recherche médicale'

Juliette Coudert

Fellow of the Ministry of Higher Education & Research

Estefania Vina Barrientos

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; 211 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; 164 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 (84 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

 

  • 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

 

  • Veerman K, Tardiveau C, Martins F, Coudert J, and Girard JP. Single-cell analysis reveals heterogeneity of high endothelial venules and different regulation of genes controlling lymphocyte entry to lymph nodes. Cell Reports, 2019, 26:3116-3131
         We reported the 1st characterization of the full-length HEV transcriptome by single cell RNA-sequencing, discovered the heterogeneity of HEV endothelial cells in homeostatic and inflamed lymph nodes and revealed important differences in the regulation of HEV genes after interruption of LTR signaling.             
     

Review 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; 296 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

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; 641 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, 709 citations in WOS)

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; 439 citations in WOS)

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; 288 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; 170 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, 75 citations in WOS, Top 1%).

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

 

  • 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 (322 citations in WOS, Top 1%)

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

 

  • Liew F. Y., Girard JP and Turnquist H. R. Interleukin-33 in health and disease. Nature Rev Immunol, 2016, 16(11), 676–689. (309 citations in WOS, Top 1%)

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. Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family. Immunological Reviews, 2018; 281: 154-168. (166 citations in WOS, Top 1%)
    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

Single cell analysis of specialized blood vessels that mediate lymphocyte entry to lymphoid organs

High endothelial venules (HEVs) are specialized blood vessels that play a critical role in immunity by allowing trafficking of lymphocytes through the different lymphoid organs of the body. HEVs are lined by endothelial cells with a plump almost cuboidal morphology. The team of Jean-Philippe Girard at the IPBS reports the first analysis of HEV endothelial cells by single-cell RNA sequencing and uncovers their molecular differences with endothelial cells from other blood vessels. This study was published in Cell Reports on March 12th 2019.

More informations ...

How allergens trigger asthma attacks

A team of Inserm and CNRS researchers from the Institute of Pharmacology and Structural Biology—or IPBS (CNRS / Université Toulouse III—Paul Sabatier)—have identified a protein that acts like a sensor detecting various allergens in the respiratory tract responsible for asthma attacks. Their study, codirected by Corinne Cayrol and Jean-Philippe Girard, is published in Nature Immunology (march 19, 2018). These scientists’ work offers hope for breakthroughs in the treatment of allergic diseases.

More informations ...

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Identification of a critical actor controlling trafficking of leukemia cells 

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Accumulation of abnormal B cells in spleen and lymph nodes is associated with resistance to treatment. A better understanding of the mechanisms controlling trafficking of leukemic cells to lymphoid organs is thus urgently needed. A research team from the Institute of Pharmacology and Structural Biology (IPBS - CNRS/Université Toulouse III - Paul Sabatier) has identified a molecule that plays a key role in the attachment of CLL cells to blood vessels in lymph nodes. These studies supported by ‘Laboratoire d’Excellence Toulouse Cancer’ (LABEX TOUCAN) and performed in close collaboration with ‘Institut Universitaire du Cancer de Toulouse (IUCT)’ and ‘Centre de Recherche en Cancérologie de Toulouse (CRCT)’, were published in BLOOD First Edition on July 10th 2015.

More informations ... 

Key step in allergic reactions revealed

By studying the mode of action of the interleukin-33 protein, an alarmin for white blood cells, a team at the Institut de Pharmacologie et de Biologie Structurale (IPBS - CNRS/Université Toulouse III - Paul Sabatier) has been able to evidence truncated forms of the protein that act as potent activators of the cells responsible for triggering allergic reactions. This breakthrough in the understanding of the mechanisms underlying allergy could have important applications in the treatment of asthma and other allergic diseases such as eczema and allergic rhinitis. Co-directed by CNRS researcher Corinne Cayrol and INSERM senior researcher Jean-Philippe Girard, this work is published in PNAS on 13 October 2014.

More informations ...

 

 

 

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A novel mechanism in the activation of IL-33 during inflammation

Inflammation is a mechanism to help the body cope with an injury, inducing repair and regeneration of the damaged tissue and getting rid of what has caused the injury (virus, bacteria or physical injury). Researchers at the Institute of Pharmacology and Structural Biology in Toulouse (CNRS/Université de Toulouse III - Paul Sabatier) have discovered a novel step in the sequence of events leading to inflammation. They have found a mechanism involved in the activation of interleukin-33 (IL-33), an IL-1 family cytokine which play critical roles in asthma, rheumatoid arthritis, inflammatory bowel diseases and cardiovascular diseases. Their findings are published in Proc Natl Acad Sci USA Early Edition of January, 16th 2012.

More informations ...

Blood vessels participate in the eradication of tumors

Breast cancer: for the first time, very specific blood vessels have been discovered in tumors. These vessels facilitate the access of certain white blood cells, known as “killer lymphocytes”, into tumor tissues and thus lead to the efficient destruction of tumors. This work, led by Jean-Philippe Girard, Inserm senior researcher at the Institut de Pharmacologie et de Biologie Structurale (CNRS/Université Toulouse III - Paul Sabatier), in collaboration with the Institut Claudius Regaud, is published in the journal Cancer Research (August 2011).

Download the press release

 

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Dendritic cells control lymphocyte entry into lymph nodes

Dendritic cells, discovered in 1973 by Ralph Steinman (2011 Nobel prize in Physiology or Medicine) and known for their role as sentinels of the immune system, have an essential function in the development of high endothelial venules (HEVs), acting as genuine entry sites of lymphocytes into lymph nodes, inflamed tissues and malignant tumors. This is what Christine Moussion and Jean-Philippe Girard(1), researchers at the Institut de Pharmacologie et de Biologie Structurale (CNRS/Université de Toulouse III - Paul Sabatier) showed in a study(2) published online in the journal Nature on November 13, 2011. A better understanding of this process could lead to major applications in the treatment of chronic inflammatory diseases and cancer.

Download the press-release

 

Corinne Cayrol, laureate of the National Academy of Medicine

On December 17th in Paris, Dr. Corinne Cayrol received the Edouard Bonnefous Prize 2019 from the National Academy of Medicine for her work on Interleukin-33 (IL-33) as an important therapeutic target for asthma, regulated by environmental allergens.

This prize rewards all work on the environment and its consequences on human health.

More information (in french)

 

 

In 2019, Jean-Philippe Girard enters the list of the most influential researchers in the world.

This highly anticipated list identifies scientists who have demonstrated significant and extensive influence in their field of expertise through the publication of several highly cited articles (Top 1%) over the past decade. This year's list continues to recognize the most influential researchers, including 23 Nobel Prize winners, three of whom were announced this year. Jean-Philippe Girard, exceptional class research director at Inserm and head of the "Vascular Biology: Endothelial cells in Immunity, Inflammation and Cancer" team at IPBS, has joined the list as a "Highly Cited Researcher in Immunology".

More information ...

Jean-Philippe GIRARD, winner of the Prize Jean Valade 2018 from ‘Fondation de France’

Jean-Philippe GIRARD, Silver Medal of the CNRS 2013, Inserm Research Director at IPBS (CNRS-University of Toulouse), will receive the Prize Jean Valade 2018 from ‘Fondation de France’ on March 28th at the Collège de France in Paris, for his work on IL-33, a major therapeutic target for asthma and allergic diseases.

 

Jean-Philippe Girard is honored for his pioneering work on the discovery and characterization of IL-33, a protein that is now recognized as a central mediator of allergic inflammation and asthma. Asthma is one of the most common chronic inflammatory diseases in humans, affecting up to 300 million people worldwide. Progress in the prevention and treatment of asthma and allergic diseases is thus urgently needed. Identification and validation of novel therapeutic targets is critical in order to develop future treatments for those who do not respond to available therapies. The work of Jean-Philippe Girard and his team over the past 15 years has significantly contributed to the current knowledge about IL-33 mechanisms of action and regulation and the validation of IL-33 as a bona fide therapeutic target for asthma and other allergic diseases, such as atopic dermatitis

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Emma Lefrançais receives the "Grand Prix Jeune Chercheur" from the FONROGA Foundation (Dec. 2018)

Emma Lefrançais, CNRS Research associate in the laboratory of Jean-Philippe Girard,  received one of the two "Grand Prix Jeune Chercheur" from the FONROGA Foundation. 
Using intravital lung imaging, Emma's work focuses on the role of IL-33 in inflammation and cellular dynamics during respiratory allergies.

 

The FONROGA Foundation supports initiatives and achievements in the fields of culture and health in the Toulouse region. Since its creation in 2016, more than €160,000 have been given to young researchers through Awards and fellowships. At IPBS, the Foundation has already given the "Grand Prix Jeune Chercheur" to three young researchers (Drs. Laure Gibot, Etienne Meunier and Emma Lefrançais).

 

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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’

 

Grants and Fellowships

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