Reducing Protein Intake to Fight Tumors More Effectively

©Brooke Lark on Unsplash

What if immune system efficacy against cancerous cells could be reinforced by a diet in which calories are not reduced but nutrients are precisely determined? This what Inserm researchers from Université Côte d’Azur, through a study of the effects of restrictive diets on tumor growth in mice, have been exploring.  They have observed that a low-protein diet restricts tumor development by increasing immune response.  The findings, to be published in Cell metabolism, have proved promising in understanding anti-tumor immunity in mice and pave the way for new studies in humans. 

Despite the recent popularity of fasting in preventing cancer, in reinforcing chemotherapy and in extending life expectancy in patients with tumors, there is no solid scientific proof to support its efficacy at present. In reality, clinical trials are virtually non-existent in humans and the findings obtained from animal models are highly debatable.  Prolonged calorie reduction can be an aggravating factor in the undernourishment and loss of muscle mass (sarcopenia) frequently associated with chemotherapy.

An Inserm team at Université Côte d’Azur decided to focus on a hypothesis by which modulating the intake of macronutrients (carbohydrates, fats and proteins) rather than that of calories, could restrict tumor growth.  The researchers compared the effect of various diets, with varying levels of carbohydrates and proteins but the same number of calories, on tumor growth in mice.  The results show that it was a low-protein and not a low-carbohydrate diet that had a positive impact on limiting tumor growth and prolonging life expectancy in mice.

Analysis of the tumor cell content of mice on a low-protein diet showed an increased quantity and more intense activity of the specific anti-tumor cells of the immune system.  The researchers observed that the restriction of tumor growth was not due to inhibited cancer cell proliferation as could be believed, but to an increased efficacy of the immune response, also known as immunosurveillance, in destroying the cancerous cells.

When studying the molecular mechanisms linked to this phenomenon, the researchers observed that this strengthened immunosurveillance was linked to tumor cell secretion of immune system alert proteins, known as cytokines. According to the study, reducing proteins in the diet renders the available quantity of certain amino acids (constituents of proteins) insufficient – and these are substances to which cancer cells are highly sensitive.  When access to amino acids is reduced, stress is triggered in the tumor cells, which then release cytokines and thereby activate a strong immune response against the tumor.

While these findings in mice are promising in terms of understanding the anti-cancer immunosurveillance activation mechanisms, several major unknowns remain to be elucidated. These include a precise definition of the protein reduction necessary and sufficient for the diet to be effective, the identification of the amino acids implicated in tumor cell stress, and the transposability of the results to humans, whose immunosurveillance and metabolism are notably different to those of mice.  Finally, ongoing human clinical trials must take into account the difficulty of imposing such a rigorous long-term diet on patients.

How do we detect danger?

Living beings are able to integrate and identify relevant sensory information, such as smells, sounds or light, in order to regulate how they behave in the presence of potential danger. This is called context discrimination. Inserm researchers based at Neurocentre Magendie in Bordeaux have recently discovered which neurons are implicated in this phenomenon and where they are located. Good news for sufferers of post-traumatic stress disorder in whom context discrimination is disrupted.

This research has been published in Neuron.

 Traumatic experiences, such as natural disasters, terrorist attacks or military combat, can lead to the development of psychiatric disorders, such as post-traumatic stress disorder (PTSD). When sufferers find themselves faced with a similar environment to that in which the traumatic event occurred, they relive the stress of the original trauma with the same intensity. In these patients, anxiety disorders are associated with context generalization.  They have indeed become incapable of integrating and identifying the relevant sensory information produced by their five senses – which is captured in the environment – in order to regulate behavioral responses. The neuronal circuits involved in this phenomenon are unknown.

A team of researchers led by Dr Cyril Herry has for the first time recently identified in mice a population of neurons implicated in context discrimination. These neurons are located in the medial prefrontal cortex.

They did this using optogenetic approaches (see boxed text), in which the activity of neuron populations is activated or inhibited so as to determine their involvement in a particular behavior. In order to evaluate the neuronal circuits implicated in context discrimination, the researchers exposed the mice to an environment comprising various sensory elements (light, smell, sound) in which they received one or more mild electric shocks in order to render them averse to that environment.

The mice were then exposed to the same environment but without the relevant sensory elements (smell, sound, light), in order to have them believe that it was non-aversive. Thanks to real-time recordings of the activity of neurons in the medial prefrontal cortex and their optogenetic manipulation, the researchers were able to identify a population of neurons specifically activated during the context discrimination.

This research shows that neuronal activity in the medial prefrontal cortex is a key element of context discrimination.

In addition, the researchers have demonstrated that this group of neurons projects specifically to the brain stem, a region directly implicated in the motor regulation of emotional behaviors.

“This research, which deepens our understanding of the neuronal activity leading to context discrimination, could contribute to the development of treatments and therapies for people with anxiety disorders” considers Dr Cyril Herry, Inserm research director and investigator of this study.

Optogenetics consists of introducing into neurons natural light-sensitive proteins, such as channelrhodopsin, an extract of algae which is sensitive to blue light, or archaerhodopsin, which is sensitive to green and yellow light. When blue light is introduced into the mouse brain by an optical fiber, activation of the channelrhodopsin generates a depolarizing current: this activates the neurons. However, if the archaerhodopsin is activated by a green or yellow light, it generates a hyperpolarizing current and the neurons are inhibited. These light-sensitive proteins expressed at neuronal membrane level are therefore capable of freely activating or inhibiting nerve impulses. This enables the researchers to identify the neuronal networks implicated in a specific task and to determine the causal role.

How allergens trigger asthma attacks

©Adobe Stock

A veritable sensor: a team of Inserm and CNRS researchers at the Institute of Pharmacology and Structural Biology (IPBS, CNRS/Paul Sabatier University – Toulouse III) has identified a protein that is able to detect various allergens in the respiratory tract, which are responsible for asthma attacks. This study, co-led by Corinne Cayrol and Jean-Philippe Girard, was published in Nature Immunology on March 19, 2018. It offers hope for breakthroughs in the treatment of allergic illnesses.  

What do mold, pollen and cockroaches have in common? Although they belong to three distinct kingdoms of the living world, they can all trigger asthma attacks in people sensitive to them. And all of them, despite their very different compositions, contain enzymes called proteases.   

The IPBS team has identified a human protein that reacts to a large number of environmental allergens: interleukin-33 (IL-33). When they enter the human respiratory tract, the allergens release their proteases. These split the IL-33 into extremely reactive fragments which trigger the chain reactions behind allergy symptoms.

This appears to be a general mechanism responsible for triggering allergic reactions. Indeed, IL-33 was shown to detect each of the 14 allergens tested, some of which are present in ambient air (several types of pollen, house dust mites, fungal spores) and others implicated in occupational asthma (such as subtilisin, found in detergents). 

These findings are all the more important because they establish a direct link between genetics and the environment. Indeed, the gene that codes for IL-33 is recognized as being one of the principal genes of asthma predisposition in humans.

Furthermore, clinical trials now under way are focusing on this protein. And they are on the right track, given this recent discovery of a single mechanism for detection of airborne allergens by IL-33. Inhibiting the production of reactive IL-33 fragments following allergen exposure could, for example, limit severe allergic reactions in asthmatic patients. 

This study was funded by the French National Research Agency (ANR). 




Mucous production in the lung following inhalation of an allergen : IL-33 sensor present (left), IL-33 sensor deactivated (right) (lung sections, mucous shown in magenta).   

Excessive mucous production is characteristic of allergic asthma. Protein IL-33, a major factor predisposing humans to asthma, detects allergen protease activity. Activated by proteases, IL-33 sets off a cascade of reactions, including mucus production, that are associated with asthma and other allergic illnesses. When IL-33 activation is inhibited (on the right), these reactions are not triggered.

© Corinne Cayrol and Jean-Philippe Girard / IPBS / CNRS-Paul Sabatier University – Toulouse III





Zika: an accurate estimation of the neurological risks in unborn children

Thanks to a study conducted in pregnant women and their unborn children during the Zika epidemic in the French territories in the Americas, researchers from Inserm, Institut Pasteur and the University Hospital of Guadeloupe have been able to accurately estimate the risk of severe neurological complications in babies. They have also determined that the first trimester of pregnancy is the period which presents the highest risk. While the overall risk is 7%, this rises to 12.7% – i.e. more than 1 in 10 children – if infection occurs during the first 3 months of pregnancy. This research has been published in the New England Journal of Medicine (NEJM).

In February 2016, faced with a drastic increase in the number of Zika infections and in order to establish a link between the virus and neurological complications, the World Health Organization (WHO) declared a “Public Health Emergency of International Concern (PHEIC)”. In March 2016, with the aid of the REACting consortium, Inserm took charge of the establishment, sponsorship and scientific follow-up of a cohort of pregnant women exposed to Zika in the French territories in the Americas, monitored by the French Antilles-French Guiana Clinical Investigation Center (Inserm CIC 1424). The objective? To study the fetal and neonatal complications associated with Zika virus infection in an epidemic situation. This cohort was funded by the French Ministry of Health and Solidarity (Exceptional Support of Research and Innovation) and included in the European ZIKAlliance[1] program.

Several thousand women who were pregnant during the Zika epidemic in the French territories in the Americas were enrolled in this cohort between March 2016 and August 2017. The article published in NEJM addresses those women from the cohort who presented with Zika virus infection confirmed by laboratory testing between March 2016 and November 2016. These women were then monitored every month until the end of their pregnancy. All complications and treatments received were recorded and if fetal abnormality was detected during an ultrasound, an additional examination by magnetic resonance imaging was performed.

The results obtained by the researchers show a 7 % rate of congenital neurological abnormalities observed in the fetuses and neonates of the cohort, which is a lot lower than that initially observed in Brazil, and close to what was observed in the US registry.

The study confirms an especially high risk in the event of infection occurring during the first trimester.

When broken down, the results show that the frequency of neurological complications is:
12.7% when the mother is infected during the 1st trimester
3.6% when the mother is infected during the 2nd trimester
5.3% when the mother is infected during the 3rd trimester

Likewise, the percentage of severe microcephaly (head circumference < -3SD) is 1.6% overall, and:
3.7% when the mother is infected during the 1st trimester
0.8% when the mother is infected during the 2nd trimester
0 when the mother is infected during the 3rd trimester

“These are the initial findings of the analyses of this cohort, given that the babies are still very young. It will be essential to monitor all the children in order to identify any later complications,” explains Bruno Hoen, physician researcher at Inserm and University Hospital of Guadeloupe and principal investigator of the study.

“Even if these complication rates are low in relation to other viral infections in pregnant women, they remain worrying given that the Zika virus can infect over 50 % of a given population in the epidemic phase”, comments Arnaud Fontanet, who heads the Emerging Diseases Epidemiology Unit at Institut Pasteur, and who is co-investigator of the study.

REACTing (REsearch and ACTion targeting emerging infectious diseases)

Inserm and its Aviesan partners have created REACTing, a multidisciplinary consortium that brings together research groups and laboratories of excellence, in order to prepare for and coordinate research to combat the health crises linked to emerging infectious diseases. Since its creation, REACTing has also set up programs centered around the Chikungunya, Ebola and Zika epidemics.

Clinical research at Inserm

The Clinical Research Unit manages sponsor activities for the clinical trials of which Inserm is a sponsor and, together with the Directorate of Health Care Supply (DGOS), jointly supervises the Clinical Investigation Centers (CIC). In 2017, he was in charge of 238 studies, including 15 European and/or international projects.


[1] ZIKAlliance is a 3-year project funded by the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No. 734548.

In the eye of the medulloblastoma

Can genes normally expressed only in the eye be activated in brain tumours? Such a phenomenon, though surprising, has been observed in certain types of medulloblastoma, paediatric tumours of the cerebellum. Researchers from the CNRS, Institut Curie, Inserm and Université Paris-Sud[1], together with researchers at St. Jude Children’s Research Hospital (Memphis, United States), have pinpointed the role of these genes in the tumour process, thus offering new therapeutic targets. Their findings appear in the 12 March 2018 edition of Cancel Cell.

Medulloblastoma is treated with a combination of surgery, radiotherapy and chemotherapy, which results in a survival rate of 80 %, albeit with significant side effects. Group 3 medulloblastoma, associated with frequent rates of recurrence and a much lower survival rate, is characterised by the expression of a gene cluster named “photoreceptor program”. Normally, these genes are only expressed in the retina, where they define photoreceptor identity and, in particular, ensure that light signals are converted into nerve impulses.

Given that they are not expressed during the normal development of the cerebellum, activation of these genes in medulloblastoma is very surprising. Aberrant differentiation programs – unrelated to the tissue in which the tumour originates – have already been found in other types of cancer but never thought to be directly involved in the tumour process.

Celio Pouponnot, CNRS researcher at the Institut Curie, together with Franck Bourdeaut, medical researcher at the Institut Curie, and Paul Northcott at St. Jude Children’s Research Hospital in Memphis, United States, decided to examine the role this “photoreceptor program” could play in a medulloblastoma.

The presence of a protein known as NRL within this “photoreceptor program” initially drew the attention of Celio Pouponnot’s team, which for many years has studied a family of proteins similar to NRL that is involved in the formation of cancers. Researchers also identified the role of another protein specific to the retina: CRX. Strikingly, this study shows that both these factors are involved in the medulloblastoma by activating key genes: CCND2, which promotes cell proliferation, and BCL2L1, which inhibits cell death (apoptosis).

The research team then used pharmacological agents to target these anti-apoptotic proteins in preclinical models by grafting human medulloblastoma cells into mice. This treatment shrunk the tumour and extended the lives of the mice, proving the potential of this therapeutic target. These results, however, cannot be directly transposed to children for whom such pharmacological agents could be toxic.

More generally, this study shows the potential benefit of studying signs of aberrant differentiations in cancer processes, highlighting a new area in cancer research.

[1] Laboratories: Normal and pathological signalling: from embryo to innovative cancer treatments (CNRS/Institut Curie/Inserm/ Université Paris-Sud); Genetics and biology of cancers (INSERM/Université Paris Descartes) and Chemistry, modelling and imagery for biology (CNRS/Institut Curie/INSERM/Université Paris-Sud)

Section of normal cerebellum (left), and cerebellum with medulloblastoma (right). The medulloblastoma expresses genes normally active in the retina only, including NRL and CRX, which play a role in the formation of the tumour. © Morgane Morabito / UMR3347 CNRS-Institut Curie-INSERM-Université Paris-Sud

A new solution for chronic pain

Neuropathic pain is a chronic illness affecting 7-10% of the population in France and for which there is no effective treatment. Researchers at the Institute for Neurosciences of Montpellier (Inserm/University of Montpellier) and the Laboratory for Therapeutic Innovation (CNRS/University of Strasbourg)[1] have uncovered the mechanism behind the onset and continuation of pain. Thanks to their discovery, they have developed an innovative treatment prototype which produces, in animal models, an immediate and long-lasting effect on pain symptoms. This study was published on March 12, 2018 in Nature Communications.

French researchers have recently revealed the unexpected role played by the molecule FLT3 in chronic pain – a molecule known for its role in various blood functions and produced by the hematopoietic stem cells which generate all blood cells. Neuropathic pain is caused by peripheral nerve lesions caused by diseases such as diabetes, cancer, or shingles, or to accident-related trauma or surgery. In this study, the researchers showed that immune cells in the blood which flood the nerve at the lesion site synthesize and release another molecule, FL, which binds with and activates FLT3, triggering a chain reaction in the sensory system, causing pain. They revealed that FLT3 induces and maintains pain by acting far upstream on other components in the sensory system which are known for making pain chronic (a phenomenon known as “chronicization”).

After discovering the role of FLT3, researchers created an anti-FLT3 molecule (BDT001) to target the FL binding site, using detailed computer analysis of three million possible configurations. This molecule blocks the connection between FL and FLT3, thereby preventing the chain of events which leads to chronic pain.  When administered to animal models, BDT001, after three hours, reduced typical neuropathic pain symptoms such as hyperalgesia, a heightened sensibility to pain, as well as allodynia, pain caused by stimuli which normally do not provoke pain, with effects lasting 48 hours after a single dose.

Neuropathic pain, which affects approximately 4 million people in France, is a debilitating disease with significant social costs. Current forms of treatment, essentially based on off-label uses of medication such as anti-depressants and anti-epileptics, are ineffective: less than 50% of patients obtain a significant reduction in their pain. Furthermore, such treatments can cause substantial side effects. The innovative therapy[2] based on this research is being developed by Biodol Therapeutics, a start-up firm which may, as a result, finalize the very first specific therapy against neuropathic pain, and, in the long term, provide relief to many people.



[1] Researchers from the Institute of Functional Genomics (CNRS/Inserm/University of Montpellier) also took part in the research.

[2] This project was financed by the French National Research Agency (ANR) and the SATT AxLR in Montpellier. INSERM licensed the patent rights resulting from this discovery (WO2011/083124 and WO 2016/016370) to Biodol Therapeutics, a new start-up operating in Montpellier and Strasbourg and supported by BPI and the Region of Occitanie.

Brain Awareness Week 2018

From March 12 to 18, 2018, for Brain Awareness Week, the general public is invited to discover the latest neuroscientific advances in an array of free events:  conferences, workshops, exhibits, film screenings, and encounters with those involved in research.

The twentieth annual Brain Awareness Week will take place in over one hundred countries and more than forty cities in France. Researchers from major research organizations, neuroscience institutes, and the realm of university hospitals will offer a fun, varied program: exhibits, film screenings, shows, conferences for the general public, workshops, debates, laboratory tours, and children’s events.

Brain Awareness Week is coordinated by the Society for Neuroscience in partnership with the Brain Research Federation, under the aegis of the European Dana Alliance for the Brain.

The event’s website:

View the 2018 program

View the press pack

Inserm website event page

Inserm, a Brain Awareness Week 2018 partner, is organizing several events throughout France with help from its researchers and regional offices. The press service provides journalists with contact information for the event’s reference researchers.

Northwest Office

Nacim Betrouni
Inserm Researcher
U1171 Degenerative and vascular cognitive disorders
+33 (0)3 20 44 64 22

David Vaudry
Inserm Researcher
“Neuropeptides, neuronal death, and cell plasticity” team leader
U1239 Neuronal and neuroendocrine differentiation and communication
+33 (0)2 35 14 67 60

Ile de France Office

Bertrand Nalpas
Inserm Researcher
Addiction mission leader
Scientific Information and Communication Department
+33 (0)1 44 23 67 65

François Rouyer
Inserm Researcher
“Molecular genetics of circadian rhythms” team leader
UMR9197 Paris-Saclay Institute of Neuroscience (NEURO-PSI)
+33 (0)1 69 82 34 36

Véronique Fabre
Inserm Researcher
U1130 Paris Seine Neuroscience
“Normal and pathologic glutamatergic neurons” team
+33 (0)1 44 27 60 68

Frédéric Laumonnier
Inserm Researcher
U930 Imaging and brain
“Neurogenetics and neurometabolomic” team
+33 (0)2 47 36 60 62

Eastern Office

Christian Gachet
Inserm Researcher
Director of Unit 949 Biology and pharmacology of blood platelets: hemostasis, thrombosis, transfusion
+33 (0)3 88 21 25 25

Nouvelle-Aquitaine Office

Philippe Zizzari
Inserm Researcher
U1215 NeuroCentre Magendie
“Energy balance and obesity” team
+33 (0)1 40 78 92 22

Deniz Dalkara
Inserm Researcher
“Gene therapies and animal models for neurodegenerative illnesses” team leader
U968 Vision institute
+33 (0)1 53 46 25 32

Occitanie-Pyrénées Office

 Patrice Peran
Inserm Researcher
“Development and validation of biomarkers in MRI and nuclear medicine” team leader
U1214 TONIC (Toulouse neuroimaging center)
+33 (0)5 62 74 61 96

Auvergne-Rhône-Alpes Office

Claude Gronfier
Inserm Researcher
U1208 Stem cell and brain research institute
 “Chronobiology and affective disorders” team
+33 (0)4 72 91 34 89

Perrine Ruby
Inserm Researcher
U1028 CRNL – Center for Research in Neuroscience in Lyon
“DYCOG – Brain dynamics and cognition” team
+33 (0)4 72 13 89 21
Email:   rf.mresni@ybur.enirrep

Sébastien Carcinella
Inserm Researcher
U1216 Grenoble Institute of Neuroscience (GIN)
“Brain stimulation and systems neuroscience” team
+33 (0)4 56 52 06 75

Occitanie Méditerranée Office

Isabelle Chaudieu
Inserm Researcher
U1061 Neuropsychiatry: epidemiological and clinical research
+33 (0)4 99 61 45 78

Marie Péquignot
Inserm Researcher
U1051 Institute for Neurosciences of Montpellier: sensory and motor deficits
“Genetics and therapy for retinal and optic nerve blindness” team
+33 (0)4 99 63 60 52

PACA Office

Christophe Bernard
Inserm Researcher
“Physiology and physiopathology of neural networks” team leader
U1106 Institute of systems neuroscience – INS
+33 (0)4 91 32 42 49

View Inserm’s latest neurosciences publications:

Susceptibility to Addiction: Poor Production of New Neurons Implicated

Compensation Mechanisms in Subjects with Alzheimer’s Disease Lesions to Preserve Their Intellectual and Memory Performance

Alcoholism and Dementia Risk

The Biological Clock Sets a Different Rhythm for Each Organ

Migraine: Regions of the Brain We Thought Felt No Pain

Des puces pour modéliser et mieux comprendre la maladie de Huntington (Chips to Model and Better Understand Huntington’s Disease – only available in French)

Susceptibility to addiction: poor production of new neurons implicated


Drug addiction behaviors and vulnerability to relapse are linked to our brain’s ability to produce new neurons. This is the finding of Inserm researchers from Neurocentre Magendie at the University of Bordeaux, after observing the behavior of mice taught to self-administer cocaine. Their results, to be published in Molecular Psychiatry, show a link between the deficient production of new neurons in the hippocampus and addiction to drugs.

In the brain, the hippocampus is one of the centers of memory. It includes the dentate gyrus, which has the particularity of producing new neurons (a phenomenon known as neurogenesis) in adults. Abnormal neurogenesis is correlated with a number of neuropsychiatric disorders, such as memory or mood disorders.

Although a link between erratic neurogenesis and drug addiction has already been suspected, there has been no scientific proof to back up this hypothesis until now. The Inserm research teams of Nora Abrous and Pier-Vicenzo Piazza from Neurocentre Magendie (Unit 1215) of the University of Bordeaux, studied the role of neurogenesis in cocaine addiction.

Two groups of mice were compared: one healthy and one genetically engineered to have reduced hippocampal neurogenesis. The mice were trained to self-administer cocaine by introducing their noses into a hole to trigger the intravenous diffusion of cocaine in their bloodstream. The number of actions that they needed to perform to obtain a similar quantity of drug was then gradually increased. The researchers observed that the transgenic mice showed greater motivation (measured in terms of number of actions in the holes) to “work” to obtain cocaine.

After several weeks of withdrawal, the mice were once again exposed to the environment in which they had learned to self-administer cocaine. It was then that the transgenic mice showed greater susceptibility to relapse by seeking once more to trigger administration of the drug.

The transition to addiction is a process combining repeated exposure to drugs and a vulnerability specific to each individual: by demonstrating that neurogenesis is a key factor in vulnerability to addiction, this research offers new perspectives in understanding individual fragility in the face of drug dependence.

This research also opens new avenues towards understanding addictive behaviors in adolescents. “Adolescence, a period of initiation into drug use, is also a time of major brain maturation, characterized in particular by extremely intense neuronal production in the dentate gyrus” specifies Nora Abrous, Inserm researcher, who had already demonstrated in 2002 the negative impact of drug use on the production and survival of new neurons in the hippocampus. She adds that “drug use, by reducing the production of these neurons, increases addiction in adolescents and renders them more vulnerable to relapse during withdrawal attempts”. In its subsequent research, her team “will try to manipulate new neurons with the help of pharmacogenetic techniques, in order to reduce the motivation of the mice for the drug and block relapse during withdrawal”.

Tattoos: are they really indelible?


Researchers from Inserm, CNRS and Aix Marseille University at the Center of Immunology Marseille-Luminy (CIML) have discovered that while a tattoo may be forever, the skin cells that carry the tattoo pigment are not. These cells transmit this pigment to new cells when they die. Acting on this process could improve current laser removal techniques. This study was published on March 6, 2018 in Journal of Experimental Medicine.

For many years, it was thought that tattoos worked by staining fibroblast cells in the dermal layer of the skin. More recently, however, researchers suggested that skin macrophages (specialized immune cells that reside in the dermis) “gobble up” the tattoo pigment, as they would normally engulf an invading pathogen or piece of a dying cell. In either case, it was presumed that the pigment-carrying cell lived forever, allowing the tattoo to be more or less permanent.

A hypothesis which has been called into question by a team of researchers from Inserm and CNRS, led by Sandrine Henri and Bernard Malissen of the Center of Immunology Marseille-Luminy which, with the help of the Marseille Center for Immunophenomics, has developed a genetically-engineered mouse capable of killing the macrophages residing in its dermis. Over the weeks that followed, the researchers observed that the thus destroyed cells had been replaced by new macrophages derived from precursor cells present in the blood and originating from the bone marrow, known as monocytes.

They found that the dermal macrophages were the only cell type to take up the pigment when they tattooed the mice’s tails. Despite the programmed death of these macrophages, the appearance of the tattoo did not change. As such, the team concluded that the dead macrophages released the pigment into their surroundings where, over the following weeks, it was taken up by new macrophages. 

©Baranska et al., 2018

The appearance of a tattoo appears to be the same before (left) and after (right) the dermal macrophages were killed.

This cycle of pigment capture, release and re-capture occurs continuously in tattooed skin, even when macrophages are not killed off in one go. The researchers transferred a piece of tattooed skin from one mouse to another and found that, after six weeks, most of the pigment-carrying macrophages were derived from the recipient rather than the donor animal.

We think that, when tattoo pigment-laden macrophages die during the course of adult life, neighboring macrophages recapture the released pigments and insure in a dynamic manner the stable appearance and long-term persistence of tattoos,” explains Sandrine Henri, Inserm researcher and co-leader of the research project.

©Baranska et al., 2018

The green pigment of the tattoo is taken up by the macrophages (left). The pigment is released when these cells are killed (center) but, 90 days later, it is taken back up into new macrophages that have replaced the old ones (right).

Tattoos can be removed by laser pulses that cause the death of the skin cells and the release and fragmentation of their pigment. The latter can then be transported away from the skin via lymphatic vessels that drain the skin. “Tattoo removal using this laser technique can be likely improved by the temporary elimination of the macrophages present in the tattoo area”, declare the researchers. “As a result, the fragmented pigment particles generated using laser pulses will not be immediately recaptured, a condition increasing the probability of having them drained away via the lymphatic vessels. “

New pediatric reference growth curves for France


Thanks to work coordinated by Inserm and its researchers at the Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), French child health and immunization record booklets (carnets de santé) distributed from April 1, 2018 will contain new reference growth curves. These curves were devised according to a totally innovative method in which over 5 million measurements collected from children aged 0 to 18 years were analyzed. As expected, the new curves for height, weight and head circumference are situated above the old ones. Numerous innovations in their presentation will help parents and doctors to monitor children’s growth.

Monitoring the growth of children is essential and can be for various purposes, such as to ascertain the suitability of nutritional intake in normal or pathological situations or detect illnesses early – conditions which can be severe in some cases.  This process involves the regular measurement of weight, height, head circumference and Body Mass Index (BMI) and the comparison of these values with reference data. The French growth curves contained in the previous version of the health and immunization record booklet date back to 1979 and were established based on the measurements of several hundred children born in the 1950s who were monitored until adult age.  It was demonstrated that these charts, as well as those proposed by the World Health Organization (WHO), are not optimal for monitoring the growth of contemporary children in France[1].

This is why the French directorate general for health tasked the researchers from Inserm unit 1153/CRESS in October 2016 to produce updated growth curves for the new edition of the record booklet. To do this, the researchers took an innovative big data approach in which a public-private partnership was formed and a massive quantity of data extracted. In total, around 5,000,000 measurements of weight, height and head circumference, from 261,000 children between the ages of 0 and 18 years were collected and analyzed. This data was obtained from 42 consenting doctors randomly-selected from the pediatrician members of the French association of ambulatory pediatrics (AFPA) and primary care physicians, taking into account the region and size of their towns and cities of practice to ensure proper representation of the entire metropolitan territory[2]. The new curves were then devised in conjunction with the representatives of the future users in order to best meet their expectations.

In practice, what has changed?

As expected, the AFPA- CRESS/Inserm -CompuGroup Medical 2018 height and weight curves are situated “markedly above” the previous ones.

For example, the median height of girls at 10 years of age in the new references is 139.5 cm versus 134.7 cm on the previous curves, i.e. an increase of almost 5 cm. Even if these differences lessen at the end of puberty, this development could theoretically lead to concern about the normality of the growth of a greater number of children. That is why it is essential to take target parental height into account in their interpretation, the formula for which has been added to the booklets.

With regard to weight, and as recommended by the French national authority for health (HAS), childhood overweight or obesity must be determined from the BMI curve rather than the weight curve.  From 2 years of age, the BMI curves represented in the booklet are those proposed by the International Obesity Task Force (IOTF). The expert committee wished to precede these with the “AFPA-Inserm/CRESS-CompuGroup Medical 2018” curves for children before 2 years of age, in order to visualize peak BMI at around 9 months.  The new reference curves must enable the early detection of conditions in apparently healthy children, without worrying their families needlessly” explains Barbara Heude, Inserm researcher who coordinated this research with Pauline Scherdel and Martin Chalumeau.

A number of other changes have also been introduced. These include various weight and height curves for boys and girls as of the 0-3 years period, different head circumference curves for boys and girls between the ages of 0 and 5 years, and the representation of a greater number of growth curves in order to monitor individual trajectories better. Finally, the booklet contains indications of the normal pubertal periods in order to encourage their use in interpreting the curves. “Short messages throughout the booklet aim to raise the awareness of parents and healthcare professionals of the importance of regular growth monitoring and emphasize the parameters to take into account when interpreting the measurements” conclude the researchers who have been working since 2016 on the preparation of these new charts and new algorithms for the early detection of growth abnormalities.

In addition to the creation of new curves which will be used daily in France, the technical and scientific exploit achieved by this low-cost big-data approach will enable other teams in other countries to reproduce and improve on this strategy to easily produce calibrated anthropometric measurements.

Given the innovative nature of the approach, the methodological and epidemiological decisions were made in consultation with an expert committee, comprising in particular the following learned societies and professional associations: French society of general medicine (SFMG), Primary care practitioners’ training association (SFTG), French society of pediatric endocrinology and diabetology (SFEDP), French-speaking group of pediatric hepatology, gastroenterology and nutrition (GFHGNP), French pediatric neurology society (SFNP), French pediatric nephrology society (SNP), the General pediatrics and Social pediatrics groups of the French pediatric society (SFP), and French association of ambulatory pediatrics (AFPA).


[1] Scherdel et al. PLoS One 2015 and Lancet Diabetes Endocrinol 2016.

[2] It was necessary to identify a network of healthcare professionals who perform regular medical monitoring of a large number of children from birth to adult age and who use the same IT system. The CRESS researchers therefore formed a public-private partnership with the French association of ambulatory pediatrics (AFPA) and the company CompuGroup Medical. That is why these new curves are named AFPA-Inserm/CRESS-CompuGroup Medical 2018.