AIRE, a key factor in the unequal impact of autoimmune diseases on men and women

Nadine Dragin, a researcher from an Inserm/UPMC/CNRS/AIM team codirected by Sonia Berrih-Aknin and Rozen le Panse at the Institute of Myology, based at Pitié-Salpêtrière Hospital, AP-HP, has demonstrated the central role of AIRE, a key factor in immune tolerance, in the unequal impact of autoimmune diseases on men and women. This work, published in The Journal of Clinical Investigation on 1 April 2016, was funded by AFM-Téléthon.


(c) Inserm / Delapierre Patrick

Autoimmune diseases result from a malfunction of the immune system that attacks normal constituents of the body known as “autoantigens.” They affect 5–8% of the population, and affect women more than men. They thus represent the fifth leading cause of death in women of childbearing age.

To explain this inequality, the researchers from the Institute of Myology focused on thymic tolerance mechanisms, i.e. this state of immune non-response to an antigen. The research teams observed that the Auto-Immune REgulator (AIRE), a key factor in immune tolerance, is less strongly expressed in women than in men.

AIRE controls the expression of tissue-specific antigens on the epithelial cells of the thymus (a lymphoid organ that produces components of the immune system in humans). On contact with epithelial cells expressing these specific antigens, potentially pathogenic cells receive signals that lead to their destruction. A decrease in AIRE expression leads to reduced expression of these specific antigens, and hence to less efficient elimination of the cells. This phenomenon is observed after puberty, when the thymus in both women and female mice expresses less AIRE than that in males, leading to poorer immune tolerance, and hence to greater susceptibility to autoimmune disease. The researchers also showed that oestrogen was the hormone responsible for this effect, since oestrogen treatment of thymic epithelial cells from humans and mice resulted in a decrease in AIRE expression in these cells.

Taken together, these results therefore indicate that, in females, oestrogen induces changes in the expression of the AIRE gene, thereby increasing the sensitivity of women to autoimmune diseases. AIRE expression levels may therefore indicate a predisposition to an autoimmune disease, and make the oestrogen level a potential therapeutic target.

How can the onset of psychosis be explained?

A research team from Paris Descartes University, Inserm and Sainte-Anne Hospital, led by Professor Marie-Odile Krebs, has demonstrated that epigenetic modifications accompany the onset of a psychotic episode in a cohort of young at-risk people aged 15–25 years. These modifications compromise systems for responding to oxidative stress and inflammation. Through this new work, the researchers have shed new light on this disease, for which the main biological explanation, before now, was based on disruption of dopamine secretion in the brain.

The study was published in Molecular Psychiatry on 26 April 2016


© fotolia

Psychotic disorders preferentially affect a young population, and have a major social impact. Several years before the onset of a true psychotic episode, certain changes in behaviour (isolation, aggressiveness), or certain non-specific (anxiety, problems with concentration or sleep) or more specific symptoms (perceptual abnormalities, fixed ideas, etc.) are generally present. Certain assessment tools have make it possible to define “at-risk mental state” criteria. Approximately one third of people with an “at-risk mental state” will develop a psychotic disorder within three years. There is therefore strong clinical relevance in understanding the physiopathological mechanisms that accompany this change, in order to better define monitoring strategies and, especially, therapeutic interventions.

To study the onset of psychosis, the team of researchers adopted an original approach: they studied modifications in the methylation profile[1] (measured using a blood sample) of young at-risk subjects (ICAAR cohort), monitored for a period of one year. They compared the profiles of individuals who had experienced a psychotic episode with profiles of those who had not become ill. Their conclusions indicate that epigenetic modifications are involved in the onset of a psychotic episode. The modifications preferentially occurred in promoters of genes involved in protection against oxidative stress, in axonal guidance and in the inflammatory response.


Dynamic epigenetic changes accompany the onset of psychosis

The study was carried out on 39 young subjects, 14 of whom developed a psychotic transition in the year following their entry into the cohort. Analyses were concerned with over 400,000 methylation sites, distributed throughout the entire genome (also known as the “methylome”). They included the temporal dimension (comparison before and after the onset of psychosis), but also required the constitution of an appropriate control group (made up of young people who sought care and/or psychological support, but who did not meet the criteria of at-risk subjects). From the start of monitoring, people who went on to develop psychosis showed hypermethylation of the GSTM5 gene promoter[2]. During monitoring, hypomethylation of the GSTT1 gene promoter was observed, and hypermethylation of the GSTP1 gene. These three genes protect against oxidative stress. Other significant modifications were found in genes associated with inflammation and axonal guidance of neurons.


Approaches to developing molecular tools for early detection and targeted therapeutic agents

These results will lead to improved understanding of the biological upheavals that accompany the onset of psychosis. Until now, disruptions in dopamine secretion at brain level were the main physiopathological explanation for psychosis. With the help of these new data, its onset may be linked to an inflammatory or oxidative stress that disrupts the balance (homeostasis) that has already been weakened by a genetic, environmental or neurodevelopmental vulnerability. These results pave the way to the development of tests for the early detection of the illness and monitoring of its progress in these at-risk populations, since this disruption of homeostasis can be easily detected via blood samples, on a repeat basis if necessary. They also point to new therapeutic strategies aimed at preventing psychotic conversion.

[1] Epigenetic modifications are represented by biochemical tags present on the DNA. They do not modify the DNA sequence, but do, however, induce changes in gene activity. The best characterised are methyl groups (CH3: one carbon atom and three hydrogen atoms) attached to the DNA.

[2] A member of the glutathione transferase family, this gene encodes key enzymes that protect against oxidative stress.

Researchers provide guidance on criteria to identify Endocrine Disruptors in the context of European legislation

The European Commission is legally required to provide criteria identifying Endocrine Disrupting Chemicals (EDCs), a process that has been blocked for almost three years, allegedly because of a lack of scientific consensus and because an impact assessment study was deemed necessary. Now, a group of 7 independent researchers from universities and research institutions from Europe and the United States* show how little controversy there is around the definition of EDCs, and that the simple logic used for the identification and regulation of carcinogens can be used for EDCs. The study is published this Monday as a commentary in the scientific journal Environmental Health Perspectives.


First, the authors demonstrate that there is wide acceptance of the World Health Organization (WHO) definition of an EDC as an exogenous substance or mixture that alters function(s) of the endocrine system [i.e. the hormonal system] and consequently causes adverse health effects in an intact organism or its progeny, populations or subgroups of the population.

Second, the authors describe the approach used for the identification of other health hazards of equivalent concern, such as carcinogens or reproductive toxicants. This identification relies on a simple categorization with 3 levels not referring to the toxicological concept of potency[1]. A similar approach not relying on potency should be used for endocrine disruptors; the 3 categories proposed by the European Commission as one of the options considered correspond to “endocrine disruptors”, “suspected endocrine disruptors” and “endocrine active substances” (substances altering the endocrine system with no evidence of the induction of an adverse health effect); these categories are judged sufficient by the researchers. Inclusion of potency or dose-response considerations would modify the spirit of the pesticides and biocides laws, which call for a hazard-based (and not a risk-based) management of pesticides if exposure is not negligible.

Finally, they state that it is not defensible to conduct an impact assessment study to determine scientific criteria. This would be a dangerous precedent, since impact assessment studies are not meant to define hazards, but to quantify the health, social and economic impacts of regulation. This is in line with the decision of the European Court of Justice (2015), which stated that “the definition of scientific criteria to identify properties disrupting the endocrine system can only be done in an objective manner based on scientific data relative to the endocrine system, independently from any other consideration, and in particular from any economic consideration”.

Authors recognize that scientific uncertainty remains with regard to the finer detail of mechanisms, the exact extent of health and environmental effects of EDCs and their impact at the population level. There are also questions around the number of substances likely to be identified as EDCs. However, filling these knowledge gaps is not required to provide scientific criteria defining EDCs.


Several years have been spent trying to issue scientific criteria defining a hazard that was actually defined some time ago (in 2002) by a state-of-the-science report from WHO. For this reason, the scientists consider that the claim of a lack of consensus among scientists was forged to justify delays in the publication of the scientific criteria. Deferring the publication of the scientific criteria can be seen as a way to postpone full application of the 2009 pesticide and 2012 biocide laws. Authors insist that impact assessment studies should not be used as an argument for postponing the publication of a scientific definition. They express concern that scientific definitions might be distorted in order to modify the spirit of a law, thereby muddling science and policy, and postpone the application of existing laws. This postponement is all the more worrying since these scientific criteria are but one of the first steps towards identifying EDCs and providing more efficient protection of public health in the European Union.


Background information

Endocrine Disrupting Chemicals (EDCs) can be very diverse in terms of chemical nature, origin or occurrence. Suspected EDCs include metals (e.g., mercury), organochlorine pesticides such as DDT or triclosan (used e.g. in tooth paste or soaps), other pesticides, dietary contaminants such as bisphenol A, phenols such as parabens (used as preservatives in cosmetics) or phthalates, which can be found in perfumes, cosmetics, medical devices, polyvinyl chloride (PVC) plastics, rainwear… Effects on health outcomes such as congenital malformations, neurodevelopment, behaviour, breast cancer, have been reported for some of these substances in animal models or human studies. The resulting health-related costs in the European Union is estimated to be in the €100-200 billion range (Trasande L et al., JCEM, 2015).

Europe is the only large economy in the world with an ambitious legislation on EDCs. In addition to other health hazards such as carcinogens, mutagens or reproductive toxicants, the European Parliament has identified EDCs as a new type of hazard for health and the environment.

A strategy on endocrine disruptors exists in the European Union since 1999, and in 2009 and 2012, the European Parliament passed two laws on pesticides and biocides (the Plant Protection Products [pesticides] Regulation in 2009 and the Biocide Products Regulation in 2012). These laws stipulated that, for compounds for which population exposure is not negligible, pesticides and biocides containing endocrine disruptors should be regulated on a hazard-based logic (as opposed to a risk-based logic). This implies that there is no need to characterize in detail the dose-response function, identify all possible health effects induced, or possible thresholds in the effects of the compound on health. This approach allows faster management of health risks and more limited resort to test animals, and avoids the debate on the plausibility of the existence of thresholds in the action of these compounds. It is also the logic planned for the management of pesticides and biocides containing carcinogens, mutagens and reproductive toxicants.

The application of the part of these laws regarding endocrine disruptors required the European Commission to publish criteria for identifying endocrine disruptors not later than 2013. This has not been done. Instead, a Roadmap listing 4 options to identify criteria was published by the European Commission in 2014 and the start of an impact assessment study aiming at supporting the choice between the 4 options announced. In December 2015, the European Court of Justice ruled that an impact assessment study was irrelevant, and urged the Commission to publish criteria without delay. The assessment done by the researchers point to the “Option 3” of the European Commission roadmap as being scientifically relevant and operational.

Since 2013, the pesticide and biocide laws (for their part relative to endocrine disruptors) could not be applied because of the lack of publication of criteria for identifying endocrine disruptors. The European Commission indicated in February 2016 that two documents, including one providing criteria for the identification of EDCs, would be published by summer 2016.

Note that, after submission of this publication, a distinct consensus workshop was held by scientists on April 11-12, 2016 in Berlin on a similar topic. The workshop was focused on more fundamental scientific notions, and concluded on the relevance of the WHO definition of EDCs, and the lack of relevance of the concept of potency to identify EDCs. More information can be found on the BfR website.


Distinction between hazard-based and risk-based regulation of chemicals (copyright RemySlama-Inserm)

distinction between hazard-based and risk-based regulation of chemicals (c) Remy Slama-Inserm

* Authors are affiliated with Inserm- Université Grenoble Alpes and CNRS-Museum national d’histoire naturelle (France); CHU Liège (Belgium) ;University of Nottingham and Brunel University London (UK), University of Torino (Italy); University of Massachusetts (USA)

[1] According to the International Union of 
Pharmacology, potency is « an expression of the activity of a drug [or toxic substance], in terms of the concentration or amount needed to produce a defined effect; an imprecise term that should always be further defined » (Neubig, Pharmacological Reviews, 2003).
Researchers point to the vagueness of this definition and recommend to use the more informative and related concept of dose-response function.

Involvement of Inserm and its Aviesan partners in research on the ZIKA virus

In the last two years, nearly 2 million people have been infected with the Zika virus in Latin America and the Caribbean. At the end of 2015, REACTing and members of the Aviesan alliance immediately became involved, particularly Inserm, Institut Pasteur, the Institute for Development Research (IRD), the French Blood Transfusion Service and the associated university hospitals. Initial contact was made with Brazilian researchers from Fiocruz in November 2015. The international Zika Summit conference, taking place at Institute Pasteur on the 25 and 26 April 2016, will review ongoing research projects:


Several observational and clinical research projects on the monitoring of symptomatic pregnant women, monitoring of children with malformation of the nervous systems or born of infected mothers, construction of biobanks of biological specimens and samples, assessment of the penetration of the virus in populations, and mathematical modelling of its dynamics, have already begun. Teams working in the neuroscience area have also been assembled to begin projects on this theme in a coordinated manner, given the neurotropic nature of the Zika virus.
More specifically, projects strongly involving the French Departments in the Americas are concerned with the following:

  • analysis of the consequences of infection during pregnancy for about 5,000 pregnant women in Guadeloupe, French Guiana and Martinique
  • expansion of the CARBO cohort, a cohort of patients with acute arbovirus infection
  • epidemiological analysis of cases of microcephaly and Guillain-Barré syndrome in French Polynesia (with strong involvement from Institut Pasteur)
  • research on sexually transmitted infection, and the persistence of the virus in semen.


In terms of diagnostics, the aim is to rapidly develop a reliable method at individual and population scale, particularly aimed at pregnant women and newborns, taking into account the variety of pathogens, particularly arboviruses, that co-circulate in countries where the Zika virus epidemic is rife.

Based on these initial elements, Inserm and its partners in the Aviesan alliance have responded to a European call for proposals. For the Aviesan partners, this means:

  • mobilising all French research forces working in the area, as well as involving all European and Latin American partners in a common approach
  • rapidly deploying innovative research, particularly on
    • Zika and the nervous system,
    • modelling the virus and its spatial configuration,
    • methods for controlling vectors,
    • the socio-economic dimension of the epidemic’s spread;
  • including partners that have already worked with European funding in similar situations, associated with dengue fever or emerging infections.

The origin of heart dysfunctions in myotonic dystrophy identified

An international team, including researchers in France at Inserm, CNRS and the University of Strasbourg, brought together at IGBMC[1] is lifting the veil on the molecular mechanisms causing heart dysfunctions in myotonic dystrophy, a genetic disease affecting one person in 8,000. This new study, published this week in Nature Communications, could contribute to discovering a treatment.

DM muscle cells

(c) Inserm/IGBMC

Myotonic dystrophy, also known as Steinert disease, is the commonest adult form of muscular dystrophy. Patients affected by this genetic condition suffer from wasting of skeletal muscles as well as arrhythmia and other cardiac dysfunctions. This is a particularly debilitating disease, for which there is currently no treatment.

Myotonic dystrophy is due to a mutation leading to the expression of RNA containing long repetitive sequences of the CUG trinucleotide. These mutated RNAs accumulate and alter regulation of alternative splicing[2] of numerous genes. Despite the significance of work already done on this disease, many points remain to be elucidated. This is true for the origin of arrhythmia and other cardiac dysfunctions, which represent the second most common cause of death in this disease.

In this new study, researchers have identified new splicing alterations in messenger RNA from heart samples of affected patients. Among these many alterations, biologists have established that those relating to the cardiac sodium channel (SCN5A) were fundamental to understanding the cardiac dysfunctions of these patients.

Scientists there clarified the molecular mechanisms leading to the alteration of SCN5A in these patients. Collaboration with Denis Furling’s team at the Institut de Myologie in Paris has enabled these cardiac alterations to be reproduced in a mouse model.

“The next step would be to see if, by restoring correct splicing of SCN5A, we can also successfully restore normal heart function”, explains Nicolas Charlet-Berguerand, Inserm Research Director, who coordinated this work. The researchers are hoping that this breakthrough will give a fresh boost to research into this rare disease.

Modèle d'épissage alternatif du canal sodique cardiaque

Alternative splicing model of the cardiac sodium channel (SCN5A) in myotonic dystrophy. (c) Inserm/IGBMC

This work was financed by the French Myopathy Association (AFM), the European research council (ERC), the European E-rare programme (ANR), Inserm and Labex-INRT (ANR).

[1] Institute of Genetics and Molecular and Cellular Biology (Inserm/CNRS/University of Strasbourg)

[2] In eukaryotes, this is a process by which RNA transcribed from a gene can undergo different cutting and splicing steps leading to the loss of various regions. This process enables proteins having distinct properties to be produced from the same gene.

Recycling an anti-hypertensive agent to fight brain tumors

Treatments available for glioblastoma—malignant brain tumors—have little effect. An international collaboration[1] led by the Laboratoire Neurosciences Paris-Seine (CNRS/ INSERM/UPMC)[2] tested active ingredients from existing medications and eventually identified one compound of interest, prazosin, on these tumors. Not only did it seem to be effective in this type of cancer, but it also acted on a signaling pathway that is common with other cancers. These promising findings are available online (advance publication) in EMBO Molecular Medicine.


(c) Fotolia

Turning old into new is what recycling is all about—and what is being attempted by an international collaboration of research scientists coordinated by Marie-Pierre Junier and Hervé Chneiweiss at the Laboratoire Neurosciences Paris-Seine (Paris). The researchers chose to study the most common malignant tumors that develop from brain cells, glioblastomas, which represent the fourth most frequent cause of cancer deaths among adults and the second in children. This is due to the inefficacy of current treatments. Indeed, a glioblastoma can resist treatment and reawaken from a very small number of tumor cells called glioblastoma-initiating cells (GIC). It is these cells—whose characteristics and properties resemble those of stem cells—that were targeted in the study.

Rather than trying to discover new compounds, the team opted for repositioning existing drugs. In other words, they tested a collection of substances used for so long to treat other conditions that their patents have now fallen into the public domain[3]. This method makes it possible to develop new active ingredients cheaply and very rapidly. Twelve hundred compounds were thus tested on normal human neural stem cells and on glioblastoma-initiating cells from different aggressive tumors.

Twelve of these compounds showed a toxic effect on GIC—and none on the normal neural stem cells. The most effective was prazosin. Tested in mice carrying glioblastoma-initiating cells, prazosin significantly reduced the size of tumors and prolonged survival of the mice by more than 50%.

This compound, which has been used for many years to treat hypertension, is an alpha-adrenergic receptor antagonist. The researchers nonetheless made a surprising finding: glioblastoma-initiating cells are devoid of these receptors. The compound therefore acts via an “off-target” mechanism, or in other words through another pathway than standard interaction. The scientists thus identified an intracellular signaling molecule, PKCδ, which is over-expressed in GIC when compared with normal neural stem cells. In the presence of prazosin, it is only cleaved in GIC, which leads to their death.


Clinical trials will be initiated this year to confirm these findings. If they are conclusive, the compound could rapidly be introduced to complement existing therapies and improve the management of patients with brain cancer. Already, the scientists have discovered that other cancer cells display altered PKCδ signaling, including those in colorectal, pancreatic and liver cancer. Understanding the mechanism of action of prazosin may therefore pave the way for the development of new potential treatments for other cancers.

[1] Including scientists from the Laboratoire d’Innovation Thérapeutique (CNRS/Université de Strasbourg), the Stanford University Institute for Stem Cell Biology and Regenerative Medicine (USA) and the Instituto Estadual do Cérebro Paulo Niemeyer in Rio de Janeiro (Brazil).

[2] This laboratory forms part of the Institut de Biologie Paris-Seine.

[3] Pharmaceutical compounds are protected by a patent for 20 years after their discovery. Because of the length of the clinical trials that are necessary before a drug can be put on the market, the duration of their patent protection does not normally exceed 10-15 years after a Marketing Authorization (MA) is granted.

A quadriplegic man regains partial use of his right hand by means of a brain implant

A patient paralysed in his hands and legs is able to use his hand through a device able to restore communication between the brain and muscles, bypassing the spinal cord. According to the French Press Association, a chip containing 96 electrodes, implanted in the patient’s brain, transmits the quadriplegic man’s thoughts to a computer that decodes them and sends commands to a sleeve that stimulates the muscles in the arm electrically.

The results of this study, conducted by researchers at the Battelle Memorial Technology Institute in Columbus and Ohio State University, are published in the journal Nature.


For a statement on this news item:

Jérémie Mattout, Inserm research officer, specialist in brain/machine interfaces

Inserm Unit 1028 Lyon Neuroscience Research Centre

+33 (0)4 72 13 89 07


New scientific evidence of sexual transmission of the Zika virus

A study by researchers from Inserm, the Paris Public Hospitals (Bichat Hospital, AP-HP), Aix-Marseille University, and the National Reference Centre for Arboviruses confirms that the ZIKA virus can be transmitted sexually. Their analyses have shown 100% genetic correlation between the form of the virus present in a man who contracted the virus in Brazil and that of a woman who had never travelled in the epidemic area, but who had sexual relations with him.

These results are published in The New England Journal of medicine.

Mosquito sucking blood on a human hand

(c) Fotolia

The ZIKA virus, a member of the Flavivirus family, is almost exclusively transmitted to humans by Aedes mosquitoes. Although Zika infection usually causes mild symptoms, it can be responsible for severe neurological complications, particularly in the infant of a woman infected while pregnant. Some indications of possible sexual transmission of the virus have been reported before now.

For the first time, and to take things further, French researchers have been able to culture the infecting virus from two people seeking a consultation for suspected ZIKA infection. Specimens of urine, saliva and blood were taken from a man who returned from Brazil, and had contracted the virus there. The same specimens were taken from a sick woman who had sexual relations with this man, but who had never travelled to an epidemic area.

While the virus was detected in the urine and saliva of the woman, analysis of the specimens showed that it was absent from the blood and saliva of the man, making it unlikely that transmission occurred by these routes. The researchers then tested his semen for the virus, and detected high viral loads at 15 days and at 3 weeks after the patient’s return from Brazil (approximately 300 million copies/ml).

The virus from both persons was individually sequenced (using a saliva sample from the woman and a semen sample from the man) for genetic analysis. Examination showed 100% correlation between the two genetic sequences.

Apart from 4 mutations, all of them “synonymous,” the nucleotide sequences both encoded an identical form of the virus.

“Our work confirms, using molecular analyses, that sexual transmission of the ZIKA virus exists, and should be taken into consideration when making recommendations, due to its persistence in the semen several weeks after infection. The period for which men should systematically have protected sexual relations (even oral) needs to be defined,” explains Yazdan Yazdanpanah.

Sunday 17 April: World Haemophilia Day

Haemophilia is a hereditary disease characterised by bleeding due to a deficiency of coagulation factors. Haemophilia A is the most widespread form, affecting one in every 5,000 boys born.[1]

The severity of the disease depends on the extent of the coagulation factor deficiency. It is described as severe when the level of coagulation factor is below 1%, moderate if it is between 1 and 5%, and mild if it is between 5 and 40%.

Although there are replacement treatments, the World Federation of Haemophilia recalls that a large majority of the world’s haemophiliacs to not have access to them for economic reasons.

World Haemophilia Day, which will be held on Sunday 17 April, is an opportunity to highlight this lack of access to treatments and care. This event is also an opportunity to draw attention to the involvement of researchers in the development of new therapies.

The team led by Cécile Denis at Inserm Unit 1176, “Hémostase, Inflammation, Thrombose,” is especially focused on the effect of mutations found in coagulation factor VIII, in order to develop adjuvant therapies and offer treatment options for mild or moderate haemophilia. These researchers are also pursuing new therapeutic approaches using modified coagulation factor X molecules.

[1] To find out more, see our “Haemophilia” information file

An invisible system to rescue the heart

Heart failure affects over one million people in France. Although the blood system is the first to have been explored for the purpose of improving heart function, a study by Inserm has revealed the potential of a secondary system that had previously received scant attention. The researchers[1] analysed the heart lymphatic system in an animal model. They showed that this system was highly impaired following a myocardial infarction. Using a biotherapy based on the injection of innovative microparticles, they succeeded in regenerating lymphatic vessels in a targeted manner. This treatment promotes lymphatic drainage, thus limiting post-infarct oedema and inflammation. Heart function is thereby improved.

These results are published in the journal Circulation.

When the heart is no longer able to provide an adequate blood supply to meet the body’s needs, we speak of heart failure (HF). This is due to an abnormality of the heart muscle that may be associated with injuries, a filling defect associated with a lung disease, deformation of the heart valves, etc. Fatigue, breathlessness and oedema are the main symptoms. While the blood system is involved in supplying blood to the organs and providing them with oxygen and nutrients, the lymphatic system (see illustration below) transports fluids together with cells of the immune system, and drains away cellular wastes.


The human lymphatic system © Inserm, Léa Lemierre

The heart lymphatic system is especially well developed (see photo below), but its role in cardiovascular diseases had received very little attention until now.


Lymphatic vessels in the rat heart visible in red by immunofluorescence © Inserm, Ebba Brakenhielm

Following a myocardial infarctus, the heart lymphatic system undergoes extensive modification. In this study, the Inserm researchers in Rouen show, in addition to this structural abnormality, a deterioration in the functioning of this system, which leads to the development of oedema and chronic cardiac inflammation. To relieve the oedema, they had the idea of stimulating the creation of new cardiac lymphatic vessels in a targeted manner.


The research team used innovative biodegradable microparticles, containing growth factors, previously developed during work on the creation of blood vessels[2]. The researchers injected rats with a new biotherapy agent, based on the release of an encapsulated growth factor specific for lymphatic vessels (VEGF-C).

“When administered to rats, the treatment accelerates the post-infarct cardiac lymphangiogenic response, and improves the lymphatic drainage of the heart in 3 weeks. As a direct effect, it reduces cardiac oedema, inflammation and fibrosis,” explains Ebba Brakenhielm, Inserm Research Fellow.

“This work, the result of 4 years of research, shows the strong involvement of this system in cardiovascular diseases. Indeed, research on these lymphatic vessels, which were previously invisible, has only been developed in the last 10 years at most, and their role in physiopathology is often ignored,” concludes Vincent Richard, Director of the Inserm laboratory in Rouen. Lymphangiogenesis (the process that guides the formation of lymphatic vessels) thus represents a significant new therapeutic approach to explore in cases of heart failure and myocardial infarctus.


[1] Inserm Unit 1096, “New pharmacological targets for endothelial protection and treatment of heart failure” (Inserm/University of Rouen)

[2] 2011: Des microcapsules innovantes pour prévenir les maladies du cœur (Innovative microparticles to prevent heart disease), developed in collaboration with a CNRS team from Reims