Epidermal barrier and keratinocyte differentiation: from normal skin to skin inflammatory diseases
Coordinator : M. SIMON
Terminal differentiation of the epidermis is an oriented process during which keratinocytes sequentially turn on and off a series of specific genes in the course of their migration to the external surface of the skin, through the spinous and granular layers. The ultimate step, or cornification, is a genuine process of programmed cell death which results in dramatic structural changes and degradation of the nucleus and cellular organelles, leading to the formation of corneocytes. These cells form the outermost cornified layer of the epidermis. Both the granular and cornified layers allow the epidermis to perform its vital function of multiple barrier between the individual and his environment through their involvement in innate immunity, their high mechanical strength, and their ability to detoxify reactive oxygen species, to limit water loss, to reduce the penetration of UV radiation and to prevent the infiltration of allergens and microorganisms.
From several decades, the objective of our team is to decipher, at the molecular level, the keratinocyte terminal differentiation program, and to know how it is impacted by the environment, and how its impairment induces skin and hair conditions. Thus our work is a continuum between basic research and translational studies. We particularly focus on ichthyoses and inflammatory diseases, including psoriasis and atopic dermatitis. In industrialized countries, the latter affect up to 20% of children and 10% of adults. They therefore represent a huge burden on health care.
Overview of our research
Molecular mechanisms of lamellar body biogenesis and secretion.
The epidermal barrier functions rely on the secretion by granular keratinocytes of the contents of tubulo-vesicular cytoplasmic structures related to lysosomes, derived from the Golgi apparatus, and called lamellar bodies. Lamellar bodies contain various enzymes, including lipases and proteases, anti-microbial peptides, corneodesmosin and lipids. Our aim is to decipher the molecular mechanisms involved in lamellar body biogenesis, trafficking and delivery.
In particular, we investigate the role of Rab family GTPases, cytoskeleton components, as well as the related signaling pathways. In previous reports, we have shown that the Rab11A GTPase and the Myosin5B actin-dependent motor are crucial for lamellar body biogenesis and trafficking. In our ongoing work, we take profit of a unique in vitro experimental model, 3D reconstructed human epidermis where gene modulation can be performed: either down regulation by using RNA interference or overexpression of mutant sequences by using vectors allowing granular keratinocyte-specific expression. Our biological read-out is currently based on biochemical studies, photonic and electronic imaging, and functional assays.
Coordinator: Dr Corinne Leprince
Lipid metabolism and epidermal barrier: from the identification of mutated genes in Autosomal Recessive Congenital Ichthyoses to the patients’ treatment.
Inherited ichthyoses are rare monogenic diseases (prevalence 13.3 per million people in Europe) that occur at birth. They cause abnormal thickening of the skin, dryness, scaling, redness, itching and painful skin fissures involving life-long disfigurement and social ostracism. All forms of ichthyosis lead to a defective epidermal barrier. Recent researches on genes causing Autosomal Recessive Congenital Ichthyoses (ARCI) highlighted the essential role of lipids from the stratum corneum, in particular ceramides, in the epidermal permeability barrier.
Our aim is to better understand the molecular basis of this lipid-based permeability barrier in healthy skin and its impairment in ichthyoses. We are studying enzymes involved in the metabolism of skin ceramides and hope to decipher their subcellular localization and regulation. We particularly focus on PNPLA1 and LIPN, encoded by two ARCI-causing genes.
Another part of our goal is the pre-clinical development of targeted therapies to treat ichthyoses. The topical replacement of the missing lipid is a promising approach to improve the defective permeability barrier encountered in ARCI. We are developing, in an international multidisciplinary collaboration with chemists and experts in skin lipids, innovative substitution systems based on skin-identical lipids encapsulated in nanostructured formulations that will be validated for rescuing the epidermal barrier using pre-clinical in vitro and animal models of ichthyosis.
We also closely collaborate with dermatologists from the South Reference Center for Rare Skin and Mucous Membrane Diseases (recruitment of patients, clinical expertise in ichthyosis) and biologists (molecular diagnosis) at the Toulouse University Hospital. We have access to a large collection of biological samples from patients with ichthyosis and perform clinical and genetic studies to expand the knowledge of the molecular bases of ARCI and help to better define the patient’s characteristics. We also aim to identify undescribed ARCI-causing genes and potentially novel actors involved in lipid metabolism by combine approaches using next generation sequencing and bio clinical analyses.
To achieve all these projects, we benefit from our longstanding experience in the analysis of the epidermal barrier at the functional and molecular levels and we are currently developing high-performance organotypic models of ichthyoses by genome editing and 3D-culture of human keratinocytes.
Coordinator: Dr Nathalie Jonca
Atopic Dermatitis: pathophysiology, epidermal barrier dysfunctions and treatments.
Atopic Dermatitis (AD) pathogenesis results from complex interactions between genetic, immunological and environmental factors. But the primary defect that drives this type 2 immune disease remains controversial. A major discovery has been that loss-of-function mutations in FLG gene are the strongest known genetic risk factor for AD. Indeed, FLG encodes filaggrin, an epidermal protein specifically expressed by differentiated keratinocytes, and essential for the epidermal barrier function. This strongly indicates that skin barrier defects play a key role in the disease, enhancing the penetration of allergens and microbes through the epidermis and systemic IgE sensitization. Our aim is to better understand the relationship between the epidermal barrierdysfunction and the environmental factors in AD, and how this may help to identify new treatments. More specifically:
1) Using biochemical in vitro assays, reconstructed human epidermis, and mouse models, we focus on the enzymes (proteases, peptidyl-arginine deiminases (PADs), etc.) involved in the complex metabolism of filaggrin and of other proteins of the S100-fused type protein family, some of them being also associated with epidermal barrier dysfunction in AD. We study how keratinocytes adapt their filaggrin metabolism to the external environment, in particular the relative humidity level.
2) Pr Marie-Christine Cadiergues from the Dermatology Department of the National Veterinary School of Toulouse and Michel Simon detail the canine AD at the molecular level, since they believe that the dog disease may be a good model for the human one. Indeed, human and canine AD share many clinical characteristics, in particular spontaneous occurrence. They also develop canine skin models, to confirm pathophysiological hypotheses and test therapeutics, both for veterinary and human medicine.
3) In collaboration with the Ophthalmology and Dermatology Departments of Toulouse Hospital and the National Reference Center for Keratoconus, we have the opportunity i) to investigate, combining transcriptomic analysis and clinical characterization, why the development of severe conjunctivitis is the major adverse effect of Dupilumab, an anti-IL4/13 receptors used to treat AD patients; and ii) to test the hypothesis that corneal epithelium defects are involved in Keratoconus pathogenesis (a rare disease whose frequency is, for unknown reason, strongly enhanced in AD patients) and not only a consequence of stromal deformation.
4) In a multi-disciplinary (chemists, cell biologists and immunobiologists) collaborative work with R Poupot (Infinity Institute) and two other CNRS teams in Toulouse, we test the possibility to use original anti-inflammatory dendrimers as drugs for topical treatment of inflammatory skin diseases including severe forms of AD and psoriasis.
Coordinator: Dr Michel Simon
Latent class analysis categorizes chronic hand eczema patients according to skin barrier impairment. Journal Article
Journal of the European Academy of Dermatology and Venereology : JEADV, 34 (7), pp. 1529–1535, 2020, ISSN: 1468-3083 (Electronic).
Incidence and risk factors for dupilumab associated ocular adverse events: a real-life prospective study. Journal Article
Journal of the European Academy of Dermatology and Venereology : JEADV, 2020, ISSN: 1468-3083 (Electronic).
Filaggrin Expression and Processing Deficiencies Impair Corneocyte Surface Texture and Stiffness in Mice. Journal Article
The Journal of investigative dermatology, 140 (3), pp. 615–623.e5, 2020, ISSN: 1523-1747 (Electronic).
Positive change in hand care habits using therapeutic patient education in chronic hand eczema. Journal Article
Contact dermatitis, 82 (1), pp. 10–17, 2020, ISSN: 1600-0536 (Electronic).
Deimination and Peptidylarginine Deiminases in Skin Physiology and Diseases. Journal Article
International journal of molecular sciences, 21 (2), 2020, ISSN: 1422-0067 (Electronic).
Peptidylarginine Deiminase Inhibitor Cl-Amidine Attenuates Cornification and Interferes with the Regulation of Autophagy in Reconstructed Human Epidermis. Journal Article
The Journal of investigative dermatology, 139 (9), pp. 1889–1897.e4, 2019, ISSN: 1523-1747 (Electronic).
The Actin-Based Motor Myosin Vb Is Crucial to Maintain Epidermal Barrier Integrity. Journal Article
The Journal of investigative dermatology, 139 (7), pp. 1430–1438, 2019, ISSN: 1523-1747 (Electronic).
The Amino-Terminal Part of Human FLG2 Is a Component of Cornified Envelopes. Journal Article
The Journal of investigative dermatology, 139 (6), pp. 1395–1397, 2019, ISSN: 1523-1747 (Electronic).
Effect of dupilumab on atopic manifestations in patients treated for atopic dermatitis in real-life practice. Journal Article
180 (6), pp. 1551–1552, 2019, ISSN: 1365-2133 (Electronic).
Refined Immunochemical Characterization in Healthy Dog Skin of the Epidermal Cornification Proteins, Filaggrin, and Corneodesmosin. Journal Article
The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society, 67 (2), pp. 85–97, 2019, ISSN: 1551-5044 (Electronic).
Management of congenital ichthyoses: European guidelines of care, part one. Journal Article
The British journal of dermatology, 180 (2), pp. 272–281, 2019, ISSN: 1365-2133 (Electronic).
Variant PADI3 in Central Centrifugal Cicatricial Alopecia. Journal Article
The New England journal of medicine, 380 (9), pp. 833–841, 2019, ISSN: 1533-4406 (Electronic).
Activography reveals aberrant proteolysis in desquamating diseases of differing backgrounds. Journal Article
Experimental dermatology, 28 (1), pp. 86–89, 2019, ISSN: 1600-0625 (Electronic).
Peptidylarginine deiminases and deiminated proteins at the epidermal barrier. Journal Article
Experimental dermatology, 27 (8), pp. 852–858, 2018, ISSN: 1600-0625 (Electronic).
Stabilization of microtubules restores barrier function after cytokine-induced defects in reconstructed human epidermis. Journal Article
Journal of dermatological science, 91 (1), pp. 87–96, 2018, ISSN: 1873-569X (Electronic).
Transcriptomic Analysis of Two Cdsn-Deficient Mice Shows Gene Signatures Biologically Relevant for Peeling Skin Disease. Journal Article
The journal of investigative dermatology, 138 (6), pp. 1431–1435, 2018, ISSN: 1523-1747 (Electronic).
KLICK syndrome: an unusual phenotype. Journal Article
British journal of dermatology, 178 (6), pp. 1445–1446, 2018, ISSN: 1365-2133 (Electronic).
Lowering relative humidity level increases epidermal protein deimination and drives human filaggrin breakdown. Journal Article
Journal of dermatological science, 86 (2), pp. 106–113, 2017, ISSN: 1873-569X (Electronic).
PNPLA1 defects in patients with autosomal recessive congenital ichthyosis and KO mice sustain PNPLA1 irreplaceable function in epidermal omega-O-acylceramide synthesis and skin permeability barrier. Journal Article
Human molecular genetics, 26 (10), pp. 1787–1800, 2017, ISSN: 1460-2083 (Electronic).
Deimination of Human Hornerin Enhances its Processing by Calpain-1 and its Cross-Linking by Transglutaminases. Journal Article
The Journal of investigative dermatology, 137 (2), pp. 422–429, 2017, ISSN: 1523-1747 (Electronic).
Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome. Journal Article
American journal of human genetics, 99 (6), pp. 1292–1304, 2016, ISSN: 1537-6605 (Electronic).
Counterregulation between thymic stromal lymphopoietin- and IL-23-driven immune axes shapes skin inflammation in mice with epidermal barrier defects. Journal Article
The Journal of allergy and clinical immunology, 138 (1), pp. 150–161.e13, 2016, ISSN: 1097-6825 (Electronic).
Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis. Journal Article
Acta dermato-venereologica, 96 (4), pp. 473–478, 2016, ISSN: 1651-2057 (Electronic).
Novel mutation in NIPAL4 in a Romanian family with autosomal recessive congenital ichthyosis. Journal Article
Clinical and experimental dermatology, 41 (3), pp. 279–282, 2016, ISSN: 1365-2230 (Electronic).
Staphylococcus aureus density on lesional and nonlesional skin is strongly associated with disease severity in atopic dermatitis. Journal Article
The journal of allergy and clinical immunology, 137 (4), pp. 1272–1274.e3, 2016, ISSN: 1097-6825 (Electronic).
Hyaluronan Does Not Regulate Human Epidermal Keratinocyte Proliferation and Differentiation. Journal Article
The Journal of biological chemistry, 291 (12), pp. 6347–6358, 2016, ISSN: 1083-351X (Electronic).
Acefylline activates filaggrin deimination by peptidylarginine deiminases in the upper epidermis. Journal Article
Journal of dermatological science, 81 (2), pp. 101–106, 2016, ISSN: 1873-569X (Electronic).
Increased expression of caspase-1 and interleukin-18 in peeling skin disease, and a novel mutation of corneodesmosin. Journal Article
Acta dermato-venereologica, 95 (8), pp. 1019–1021, 2015, ISSN: 1651-2057 (Electronic).
Defects of corneocyte structural proteins and epidermal barrier in atopic dermatitis. Journal Article
Biological chemistry, 396 (11), pp. 1163–1179, 2015, ISSN: 1437-4315 (Electronic).
In a three-dimensional reconstructed human epidermis filaggrin-2 is essential for proper cornification. Journal Article
Cell death & disease, 6 (2), pp. e1656, 2015, ISSN: 2041-4889 (Electronic).
Knockdown of filaggrin in a three-dimensional reconstructed human epidermis impairs keratinocyte differentiation. Journal Article
The Journal of investigative dermatology, 134 (12), pp. 2938–2946, 2014, ISSN: 1523-1747 (Electronic).
Bleomycin hydrolase downregulation in lesional skin of adult atopic dermatitis patients is independent of FLG gene mutations. Journal Article
The Journal of allergy and clinical immunology, 134 (6), pp. 1459–1461.e7, 2014, ISSN: 1097-6825 (Electronic).
Analysis of protein-protein interaction between late cornified envelope proteins and corneodesmosin. Journal Article
The journal of investigative dermatology, 23 (10), pp. 769–771, 2014, ISSN: 1600-0625 (Electronic).
Topographical and nano-mechanical characterization of native corneocytes using atomic force microscopy. Journal Article
Journal of dermatological science, 75 (1), pp. 63–65, 2014, ISSN: 1873-569X (Electronic).
Mice deficient for the epidermal dermokine $beta$ and $gamma$ isoforms display transient cornification defects. Journal Article
Journal of cell science, 127 (Pt 13), pp. 2862–2872, 2014, ISSN: 1477-9137 (Electronic).
High TMEM45A expression is correlated to epidermal keratinization. Journal Article
Experimental dermatology, 23 (5), pp. 339–344, 2014, ISSN: 1600-0625 (Electronic).
Skin barrier in atopic dermatitis. Journal Article
Frontiers in bioscience (Landmark edition), 19 , pp. 542–556, 2014, ISSN: 1093-4715 (Electronic).
Identification of the first nonsense CDSN mutation with expression of a truncated protein causing peeling skin syndrome type B. Journal Article
The British journal of dermatology, 169 (6), pp. 1322–1325, 2013, ISSN: 1365-2133 (Electronic).
Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin. Journal Article
The Journal of allergy and clinical immunology, 131 (4), pp. 1094–1102, 2013, ISSN: 1097-6825 (Electronic).
Expression profile of cornified envelope structural proteins and keratinocyte differentiation-regulating proteins during skin barrier repair. Journal Article
The British journal of dermatology, 166 (6), pp. 1245–1254, 2012, ISSN: 1365-2133 (Electronic).
In vivo quantification of epidermis pigmentation and dermis papilla density with reflectance confocal microscopy: variations with age and skin phototype. Journal Article
Experimental dermatology, 21 (4), pp. 281–286, 2012, ISSN: 1600-0625 (Electronic).
Factors influencing quality of life in patients with inherited ichthyosis: a qualitative study in adults using focus groups. Journal Article
The British journal of dermatology, 166 (3), pp. 646–648, 2012, ISSN: 1365-2133 (Electronic).
Update on the epidermal differentiation complex. Journal Article
Frontiers in bioscience (Landmark edition), 17 , pp. 1517–1532, 2012, ISSN: 1093-4715 (Electronic).
A novel mutation in CDSN causes peeling skin disease in a patient from Morocco. Journal Article
British journal of dermatology, 165 (5), pp. 1152–1155, 2011, ISSN: 1365-2133 (Electronic).
Short- and medium-term efficacy of specific hydrotherapy in inherited ichthyosis. Journal Article
The British journal of dermatology, 165 (5), pp. 1087–1094, 2011, ISSN: 1365-2133 (Electronic).
Deimination of human filaggrin-2 promotes its proteolysis by calpain 1. Journal Article
The Journal of biological chemistry, 286 (26), pp. 23222–23233, 2011, ISSN: 1083-351X (Electronic).
Protease sensitivity of corneodesmosin variants encoded by the six more common CDSN haplotypes. Journal Article
The journal of investigative dermatology, 131 (6), pp. 1381–1384, 2011, ISSN: 1523-1747 (Electronic).
Hornerin is a component of the epidermal cornified cell envelopes. Journal Article
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 25 (5), pp. 1567–1576, 2011, ISSN: 1530-6860 (Electronic).
Corneodesmosomes and corneodesmosin: from the stratum corneum cohesion to the pathophysiology of genodermatoses. Journal Article
European journal of dermatology : EJD, 21 Suppl 2 , pp. 35–42, 2011, ISSN: 1167-1122 (Print).
The ubiquitous dermokine delta activates Rab5 function in the early endocytic pathway. Journal Article
PloS one, 6 (3), pp. e17816, 2011, ISSN: 1932-6203 (Electronic).
A large-scale multi-technique approach identifies forty-nine new players of keratinocyte terminal differentiation in human epidermis. Journal Article
Experimental dermatology, 20 (2), pp. 113–118, 2011, ISSN: 1600-0625 (Electronic).
The 3'-UTR AACCins5874 in the stratum corneum chymotryptic enzyme gene (SCCE/KLK7), associated with atopic dermatitis; causes an increased mRNA expression without altering its stability. Journal Article
Journal of dermatological science, 61 (2), pp. 131–133, 2011, ISSN: 1873-569X (Electronic).
Deimination and expression of peptidylarginine deiminases during cutaneous wound healing in mice. Journal Article
European journal of dermatology : EJD, 21 (3), pp. 376–384, 2011, ISSN: 1167-1122 (Print).
Prevalence and risk factors for xerosis in the elderly: a cross-sectional epidemiological study in primary care. Journal Article
Dermatology (Basel, Switzerland), 223 (3), pp. 260–265, 2011, ISSN: 1421-9832 (Electronic).
Dr N. GAUDENZIO, Institut Infinity, Toulouse
Dr N. FAZILLEAU, Institut Infinity, Toulouse
Pr R. POUPOT, Institut Infinity, Toulouse
Pr B. VELAS, Gérontopole, CHU de Toulouse
Pr N. MERBAHI, Laboratoire LAPLACE, Toulouse
Dr V. PLANAT, Laboratoire RESTORE, Toulouse
Pr T. LEVADE, Centre de Recherches en Cancérologie de Toulouse
Dr C.-O. TURRIN, Laboratoire de Chimie de Coordination, Toulouse
Dr M. BLANZAT, Laboratoire des Interactions Moléculaires et Réactivité Chimique et Photochimique, Toulouse
Dr S. BESSOU-TOUYA et Dr H. DUPLAN, Pierre Fabre Dermo-Cosmétique, Toulouse
Dr P. DESCARGUES, Genoskin, Toulouse
Dr M. HAFTEK, Université Lyon 1, Lyon
Dr D. PIN, Ecole Nationale Vétérinaire de Lyon
Dr S. PAIN, BASF Beauty Care Solutions France, Lyon
Pr B. VABRES, Service d’Ophtalmologie, CHU de Nantes
Dr D. BERNARD, L’Oréal, Paris
Pr Y. POUMAY, Laboratoire de physiologie moléculaire (URPHYM), Université de Namur, Belgique
Dr S. KEZIC, University of Amsterdam, Coronel Institute of Occupational Health, Amsterdam, Netherlands
Dr J. LYSELL, Dermatology and Venereology division, Karolinska Institutet in Stockholm, Sweden
Pr R. BETZ, Institute of Human Genetics, University of Bonn, Germany
Pr R. SANDHOFF, Department of Cellular and Molecular Pathology, German CanCer Research Centre (DKFZ), Heidelberg, Germany
Pr G. SOTIROPOULOU, Department of Pharmacy, School of Health Sciences, University of Patras, Greece
Pr L. OPALKA, Department of Inorganic and Organic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Czech Republic
Pr E. SPRECHER, Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Pr P. THOMPSON Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
European Epidermal Barrier Research Network (E2BRN ; www.e2brn.net)
Impact on the society
Our team aims to decipher the molecular determinants of this physical, biochemical and immunological barrier to the external environment that is the epidermis. At the same time, we try to understand how alterations in the epidermal barrier are responsible for several skin diseases, some very rare such as ichthyoses, others very common such as eczema. The ultimate goal is to discover new treatment options. To do this, we develop innovative experimental models and collaborate with clinical services and two Rare Disease Reference Centre at the Toulouse University Hospital.
Our team is made up of statutory and young CDD staff from a wide range of backgrounds (medical, scientific, veterinary, academic, school of engineering, etc.). It is based on complementary expertise in immunology, cellular and molecular biology, biochemistry and genetics. The resulting scientific environment allows fundamental and translational research to be developed.
We enjoy a strong international visibility in the field of dermatology. We were able to build a vast network of national, European and non-European academic collaborations, and multiple partnerships with major industrial groups (Pierre Fabre Dermo-Cosmétique, L’Oréal and BASF) and local private companies (Silab, Synelvia, Genoskin, etc.). Several patents are also operated under license with royalties that contribute to the financing of our research. These interactions with the industrial world and our projects with high valuation potential are strongly supported by Inserm Transfert, Toulouse Tech Transfer and the Occitanie/ Pyrénées – Méditerranée Region.
Many of us actively participate in the teachings of the Faculty of Medicine in Toulouse, and we regularly form to the research careers young scientists, PhD students and trainees of all levels.
- Véronique Adoue
- Laura Cau
- Fanny Coudane
- Sophie Garrido-Lagarrigue
- Julie Henry
- Marina Le Lamer
- Émilie Leclerc
- Tatiana Lupasco
- Alicia Mallet
- Nicolas Mattuzzio
- Laurence Pellerin
- Marie Reynier
- Eve Toulza
- Sara Zaafouri
- Cécile Caubet
- Chiung-Yueh Hsu
- Sohna Keita Alassane
- Rachida Nachat
- Valérie Pendaries
- Mélanie Pichery