Publications by authors named "Daniel Redoules"

24 Publications

  • Page 1 of 1

Ca1.4 calcium channels control cytokine production by human peripheral T17 cells and psoriatic skin-infiltrating T cells.

J Allergy Clin Immunol 2021 Oct 13. Epub 2021 Oct 13.

Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291, Centre National de la Recherche Scientifique UMR5051, University Paul Sabatier Toulouse III, Toulouse, France. Electronic address:

Background: Type-17 inflammation characterizes psoriasis, a chronic skin disease. Because several inflammatory cytokines contribute to psoriasis pathogenesis, inhibiting the simultaneous production of these cytokines in T17 cells may be beneficial in psoriasis. We found that Ca1.4, encoded by CACNA1F, was the only Ca1 calcium channel expressed in T17 cells.

Objective: We sought to investigate the role of Ca1.4 expression in early T17-activation events and effector functions, as well as its association with T17 signature genes in lesional psoriatic (LP) skins.

Methods: Transcriptional gene signatures associated with CACNA1F expression were examined in LP skins by RT-PCR and in situ hybridization. Ca1 inhibitor and/or shRNA lentivectors were used to assess the contribution of Ca1.4 in T17 activation and effector functions in a 3-dimensional skin reconstruction model.

Results: CACNA1F expression correlated with inflammatory cytokine expression that characterizes LP skins and was preferentially associated with RORC expression in CD4 and CD4 cells from LP biopsies. Nicardipine, a Ca1 channel antagonist, markedly reduced inflammatory cytokine production by T17 cells from blood or LP skin. This was associated with decreased TCR-induced early calcium events at cell membrane and proximal signaling events. The knockdown of Ca1.4 in T17 cells impaired cytokine production. Finally, Ca1 inhibition reduced the expression of the keratinocyte genes characteristic of T17-mediated psoriasis inflammation in human skin equivalents.

Conclusions: Ca1.4 channels promote T17-cell functions both at the periphery and in inflammatory psoriatic skin.
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http://dx.doi.org/10.1016/j.jaci.2021.09.030DOI Listing
October 2021

IL-17 Mast Cell/T Helper Cell Axis in the Early Stages of Acne.

Front Immunol 2021 28;12:740540. Epub 2021 Sep 28.

Inserm, U1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse, France.

Acne is a multifactorial disease driven by physiological changes occurring during puberty in the pilosebaceous unit (PSU) that leads to sebum overproduction and a dysbiosis involving notably . These changes in the PSU microenvironment lead to a shift from a homeostatic to an inflammatory state. Indeed, immunohistochemical analyses have revealed that inflammation and lymphocyte infiltration can be detected even in the infraclinical acneic stages, highlighting the importance of the early stages of the disease. In this study, we utilized a robust multi-pronged approach that included flow cytometry, confocal microscopy, and bioinformatics to comprehensively characterize the evolution of the infiltrating and resident immune cell populations in acneic lesions, beginning in the early stages of their development. Using a discovery cohort of 15 patients, we demonstrated that the composition of immune cell infiltrate is highly dynamic in nature, with the relative abundance of different cell types changing significantly as a function of clinical lesion stage. Within the stages examined, we identified a large population of CD69 CD4 T cells, several populations of activated antigen presenting cells, and activated mast cells producing IL-17. IL-17 mast cells were preferentially located in CD4 T cell rich areas and we showed that activated CD4 T cells license mast cells to produce IL-17. Our study reveals that mast cells are the main IL-17 producers in the early stage of acne, underlying the importance of targeting the IL-17 mast cell/T helper cell axis in therapeutic approaches.
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http://dx.doi.org/10.3389/fimmu.2021.740540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506309PMC
September 2021

High bacterial colonization and lipase activity in microcomedones.

Exp Dermatol 2020 02;29(2):168-176

Bordeaux Imaging Center, Bordeaux, France.

Background: Although acne vulgaris has a multifactorial aetiology, comedogenesis and bacteria colonization of the pilosebaceous unit are known to play a major role in the onset of inflammatory acne lesions. However, many aspects remain poorly understood such as where and when is the early stage of the Propionibacterium acnes colonization in follicular unit? Our research aimed at providing a precise analysis of microcomedone's structure to better understand the interplay between Propionibacterium acnes and follicular units, and therefore, the role of its interplay in the formation of acne lesions.

Methods: Microcomedones were sampled using cyanoacrylate skin surface stripping (CSSS). Their morphology was investigated with multiphoton imaging and their ultrastructure with scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Bacterial lipase activity in the microcomedones was quantified using a dedicated enzymatic test as well as a Fourier Transform Infra-Red (FTIR) analysis. The porphyrin produced by bacteria was analysed with HPTLC and fluorescence spectroscopy.

Results: The imaging analysis showed that microcomedones' structure resembles a pouch, whose interior is mostly composed of lipids with clusters of bacteria and whose outer shell is made up of corneocyte layers. The extensive bacteria colonization is clearly visible using TEM. Even after sampling, clear lipase activity was still seen in the microcomedone. A high correlation, r = .85, was observed between porphyrin content measured with HPTLC and with fluorescence spectroscopy. These observations show that microcomedones, which are generally barely visible clinically, already contain a bacterial colonization.
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http://dx.doi.org/10.1111/exd.14069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586799PMC
February 2020

Positive change in hand care habits using therapeutic patient education in chronic hand eczema.

Contact Dermatitis 2020 Jan 7;82(1):10-17. Epub 2019 Oct 7.

Dermatology and Allergology Department, Larrey Hospital, Toulouse University, Toulouse, France.

Background: Chronic hand eczema (CHE) is a major burden for patients. Maintenance treatment involves prevention measures limiting detrimental behaviour and aggravating factors.

Objective: To evaluate the effect of a standardised care program including therapeutic patient education (TPE) on hand care behaviours, clinical severity, quality of life, and work productivity.

Methods: A single-centre study was conducted prospectively. Together with the prescription of a topical steroid, patients participated in individual TPE sessions. Evaluations were performed initially and repeated three months after the therapeutic intervention. They included a structured analysis of hand care behaviours, the assessment of the mTLSS (modified Total Lesion Symptom Score), DLQI (Dermatology Life Quality Index), and WPAI (Work Productivity and Activity Impairment).

Results: Seventy-one patients were included (30 men, 42.3%). Three months after completion of the standardised care program, hand care behaviours such as hand washing and rinsing, hand drying, wearing protective gloves, using moisturizing creams, and following specific treatments and recommendations for CHE improved significantly in the 58 patients who completed the study and were associated with a significant improvement in the mTLSS, DLQI, and WPAI scores.

Conclusions: TPE helps patients change their hand care behaviours and adopt skin protection measures, and may improve CHE severity, quality of life, and work productivity.
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http://dx.doi.org/10.1111/cod.13390DOI Listing
January 2020

Effect of thermal spring water on human dendritic cell inflammatory response.

J Inflamm Res 2019 22;12:181-194. Epub 2019 Jul 22.

INSERM U1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse F-31037, France.

Background: Hydrotherapy appears as a valuable therapeutic tool in the management of patients suffering from chronic skin inflammatory diseases. Nevertheless, the underlying immune mechanisms of these beneficial effects remain poorly understood. To better understand the biological effects of thermal spring water on the immune system, we investigated the effects of Avène thermal spring water (ASW) on dendritic cells as key cells participating in the control of the immune response.

Methods: Dendritic cells (DCs) were generated from human monocytes and matured with LPS in ASW-based culture medium or in dexamethasone supplemented culture medium as an anti-inflammatory treatment. The phenotypes and abilities of these DCs to produce cytokines and induce allogeneic T cell response was next assessed.

Results: We showed that ASW modulated the differentiation of monocytes into DCs and impacted the DC maturation upon LPS priming. We observed a reduction of the CD83, CD86, CD1a and HLA-DR molecule expression and a decrease of IL-12 and IL-23 production whereas IL-10 production was increased. LPS-primed DCs generated in presence of ASW exhibited a reduced capacity to induce naive CD4 T cell proliferation and IFN-γ and IL-17 production.

Conclusion: Our study showed that ASW is endowed with an immunomodulatory potential. ASW limits the DC stimulatory capacity of Th1 and Th17 cell responses by impairing their maturation, IL-12 and IL-23 production and accessory cell function.
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http://dx.doi.org/10.2147/JIR.S213594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660632PMC
July 2019

Inhibitory checkpoint receptors control CD8 resident memory T cells to prevent skin allergy.

J Allergy Clin Immunol 2019 06 15;143(6):2147-2157.e9. Epub 2019 Jan 15.

CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France; INSERM, U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; CNRS, UMR 5308, Lyon, France. Electronic address:

Background: Tissue-resident memory T (Trm) cells are detrimental in patients with numerous chronic inflammatory diseases, including allergic contact dermatitis (ACD).

Objectives: We sought to analyze the contribution of Trm cells to the chronicity and severity of ACD and to define the local parameters regulating their development and functions.

Methods: We used an experimental model of ACD (ie, contact hypersensitivity to 2,4-dinitrofluorobenzene) that is mediated by CD8 T cells.

Results: Our data show that early effector T cells accumulated in the skin during the acute contact hypersensitivity reaction and gave rise to epidermal CD8 Trm cells expressing a specific set of inhibitory checkpoint receptors (ICRs), such as programmed cell death protein 1 (PD-1) and T cell immunoglobulin and mucin domain 3 (TIM-3). Those Trm cells remained in the epidermis for several weeks and mediated the eczema exacerbations, which developed on allergen re-exposure without the contribution of circulating specific T cells. Furthermore, allergen-induced Trm cell reactivation was constrained because treatment with ICR antagonists dramatically enhanced the magnitude and severity of eczema exacerbations. Finally, we show that the persistence of the allergen in the epidermis for long periods of time was responsible for both the development and maintenance of epidermal Trm cells, as well as the sustained expression of ICRs.

Conclusion: Although CD8 Trm cells are key for the pathophysiology of ACD, intrinsic mechanisms control their reactivation to prevent damaging immunopathology. Developing strategies targeting the reactivation of skin Trm cells in situ through their ICRs should open new perspectives for the treatment of ACD.
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http://dx.doi.org/10.1016/j.jaci.2018.11.048DOI Listing
June 2019

Stabilization of microtubules restores barrier function after cytokine-induced defects in reconstructed human epidermis.

J Dermatol Sci 2018 Jul 18;91(1):87-96. Epub 2018 Apr 18.

Centre de Biologie du Développement, Université Paul Sabatier/CNRS, 31062, Toulouse, France. Electronic address:

Background: A variety of human skin disorders is characterized by defects in the epidermal barrier, leading to dehydration, itchiness, and rashes. Previously published literature suggests that microtubule stabilization at the cortex of differentiating keratinocytes is necessary for the formation of the epidermal barrier.

Objectives: We tested whether stabilization of microtubules with paclitaxel or epothilone B can repair barrier defects that were experimentally induced in three-dimensional culture models of epidermis.

Methods: We established two models of defective epidermis in vitro, using three-dimensional cultures of primary human keratinocytes on filter supports: immature reconstructed human epidermis (RHE), and RHE that was compromised by treatment with inflammatory cytokines, the latter mimicking defects seen in atopic dermatitis.

Results: Both paclitaxel and epothilone B promoted keratinocyte differentiation, accumulation of junctional proteins at the cell cortex, and the early appearance of lamellar bodies in immature RHE, whereas destabilization of microtubules by nocodazole had the reverse effect. Moreover, stabilization of microtubules rescued the barrier after cytokine treatment. The rescued barrier function correlated with the restoration of filaggrin and loricrin protein levels, the cortical accumulation of junctional proteins (E-cadherin, β-catenin, and claudin-1), and with the secretion of lamellar bodies.

Conclusions: Our data suggest that the microtubule network is important for the formation of the epidermis, and that stabilization of microtubules promotes barrier formation. Microtubule stabilization may support regeneration of damaged skin, by restoring or improving the barrier.
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http://dx.doi.org/10.1016/j.jdermsci.2018.04.008DOI Listing
July 2018

Visualization of dendritic cells' responses in atopic dermatitis: Preventing effect of emollient.

Exp Dermatol 2018 04 18;27(4):374-377. Epub 2017 Dec 18.

Skin Research Center, Pierre Fabre Dermo-Cosmétique, Toulouse, France.

Atopic dermatitis (AD) is a chronic and multifactorial inflammatory skin disease involving various dendritic cells such as epidermal Langerhans cells (LC) and inflammatory dendritic epidermal cells (IDECs). Most of the clinical studies was performed on isolated cells, and thus, it would be useful to characterize directly on the human epidermal tissue the first cellular events occurred during the AD. The suction blister method was used to obtain whole epidermis samples and interstitial cutaneous fluids. Employing multiphoton microscopy, we analyzed the early dynamic behavior of inflammatory cells using Dermatophagoides pteronyssinus atopy patch test (Derp-APT) and evaluated the effects of emollient pre-application. Derp-APT application provoked rapid and strong infiltration of IDECs, and proliferation and activation of LC in the AD subjects' epidermis. Moreover, emollient pre-application strengthened the defective skin barrier and had positive effects on inflammatory cells' behavior, characterized by the complete inhibition of IDEC influx and the presence of immature LC.
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http://dx.doi.org/10.1111/exd.13470DOI Listing
April 2018

Proteomic and transcriptomic investigation of acne vulgaris microcystic and papular lesions: Insights in the understanding of its pathophysiology.

Biochim Biophys Acta Gen Subj 2017 Mar 24;1861(3):652-663. Epub 2016 Oct 24.

Université de Lille 1, INSERM U1192 - Laboratoire Protéomique, Réponse Inflammatoire & Spectrométrie de Masse (PRISM), F-59000 Lille, France. Electronic address:

Background: The pathogenesis of acne vulgaris involves several phases including androgen-dependent hyper-seborrhea, colonization by Propionibacterium acnes, and inflammation. Recent investigations have shown that in fact P. acnes provokes the activation of the inflammasome present in macrophages and dendritic cells. This signaling pathway leads to excessive production of interleukin IL-1β, a proinflammatory cytokine. Nevertheless, these well-studied phenomena in acne fail to elucidate the mechanisms responsible for the appearance of different lesions.

Methods: We investigate response pathways for specific acne lesions such as microcysts and papules using shot-gun proteomic followed by systemic biology and transcriptomic approaches.

Results: Results show that most of the proteins identified as differentially expressed between the normal and acne tissue biopsies associated with the immune system response were identified as highly or exclusively expressed in the papule biopsies. They were also expressed in microcysts, but in lower amounts compared to those in papules. These results are supported by the identification of CAMP factor protein produced by P. acnes in microcysts, indicating its enhanced proliferation in this type of lesion CONCLUSIONS: As CAMP factor protein was not detected in papule biopsies, we can see a clear delineation in the stages of progression of acne pathogenesis, which begins with a hyphenated inflammatory response in the papule stage, followed by imbalance of lipid production, which in turn triggers the enhanced proliferation of P. acnes.

General Significance: We demonstrate that expression inflammation varies across the two types of lesions, suggesting different pathways enhanced as a function of the progression of P. acnes.
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http://dx.doi.org/10.1016/j.bbagen.2016.10.021DOI Listing
March 2017

Aquaphilus dolomiae extract counteracts the effects of cutaneous S. aureus secretome isolated from atopic children on CD4 T cell activation.

Pharm Biol 2016 Nov 14;54(11):2782-2785. Epub 2016 May 14.

a INSERM UMR 1043, CNRS UMR 5282, Université Toulouse III Paul Sabatier , Toulouse , France.

Context: Skin microbiota takes part in the control of cutaneous inflammation. In skin diseases such as atopic dermatitis (AD) cutaneous dysbiosis and the emergence of Staphylococcus aureus contribute to the pathophysiology of the disease. New therapeutic approaches consist in topical application of natural products able to counteract S. aureus effects through activation of resident immune cells producing anti-inflammatory cytokines such as IL-10.

Objective: This study investigates the potential immunosuppressive properties of Aquaphilus dolomiae (Neisseriaceae), a flagellated bacterium contained in Avène Thermal Spring Water used in hydrotherapy treatments of AD patients.

Materials And Methods: An aqueous protein extract of Aquaphilus dolomiae (ADE, 60 μg/mL) was added to human monocyte-derived dendritic cells (moDC) for 24 h. Expression of HLA-DR, CD86 and CD83 was evaluated by flow cytometry and released cytokines (IL-10, IL-12) by cytometry bead array assay. The proliferation of allogeneic CFSE-labelled CD4T cells stimulated with ADE-conditioned moDC and S. aureus secretome was analysed by flow cytometry.

Results: MoDC exposed to ADE expressed lower levels of HLA-DR and CD86 than untreated cells, no CD83 and secreted barely detectable IL-12 but high amounts of IL-10 (N = 12, p < 0.0002). The proliferative effect of S. aureus secretome on CD4T cells was reduced (p < 0.001) in the presence of ADE-moDC.

Conclusion: ADE counteracted the mitogenic effect of a S. aureus secretome on CD4T cells. Owing to the role of S. aureus colonization in driving inflammation in AD the immunosuppressive property of the ADE might be useful to reduce disease severity.
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http://dx.doi.org/10.3109/13880209.2016.1173069DOI Listing
November 2016

Effects of a New Emollient-Based Treatment on Skin Microflora Balance and Barrier Function in Children with Mild Atopic Dermatitis.

Pediatr Dermatol 2016 Mar-Apr;33(2):165-71

European Center for Skin Research, Pierre Fabre Dermo-Cosmétique, Toulouse, France.

Background/objectives: The use of emollients is widely recommended for the management of atopic dermatitis (AD), especially between flares. An imbalance of skin microflora is suspected of playing a key role in exacerbations of AD. Our aim was to evaluate the effect of a new emollient balm on clinical parameters (SCORing Atopic Dermatitis [SCORAD], xerosis, pruritus), skin barrier function (transepidermal water loss and loricrin, filaggrin, corneodesmosin, and involucrin expression], skin microflora biodiversity, and Staphylococcus aureus and Staphylococcus epidermidis balance in children with mild AD.

Methods: Fifty-four children (1-4 yrs old) were enrolled in this randomized, controlled study. Subjects applied a hygiene product and the emollient balm (emollient group, n = 28) or the hygiene product only (control group, n = 26) twice a day for 28 days.

Results: We found improvement in favor of the emollient group in SCORAD (p < 0.001), pruritus (p = 0.06), and xerosis (p = 0.06) after 28 days of application. Moreover, transepidermal water loss decreased in the emollient group by 34% (p = 0.06) and involucrin expression by 37% (p = 0.001) at day 28 from baseline in association with improvement in barrier function, whereas other barrier-specific proteins did not vary. S. aureus increased significantly in the control group only (6.5 times, p = 0.01), whereas S. epidermidis remained stable in both groups. The Shannon index (H' = 2.3) did not vary with treatment in either group.

Conclusion: Twice-daily application of a new emollient balm in children with mild AD protected the skin from S. aureus proliferation and preserved microflora biodiversity.
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http://dx.doi.org/10.1111/pde.12786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071726PMC
January 2017

Staphylococcus aureus density on lesional and nonlesional skin is strongly associated with disease severity in atopic dermatitis.

J Allergy Clin Immunol 2016 Apr 11;137(4):1272-1274.e3. Epub 2015 Nov 11.

Department of Dermatology, Toulouse University, Hôpital Larrey, Toulouse, France; CNRS (Centre National de la Recherche Scientifique) UMR5165, Toulouse, France; INSERM U1056, Toulouse, France; University of Toulouse, UDEAR (Unité Différenciation Epidermique et Autoimmunité Rhumatoïde), Toulouse, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2015.07.052DOI Listing
April 2016

Effects of the Staphylococcus aureus and Staphylococcus epidermidis Secretomes Isolated from the Skin Microbiota of Atopic Children on CD4+ T Cell Activation.

PLoS One 2015 28;10(10):e0141067. Epub 2015 Oct 28.

INSERM UMR 1043, CNRS UMR 5282, Université Toulouse III Paul Sabatier, Toulouse, France.

Interactions between the immune system and skin bacteria are of major importance in the pathophysiology of atopic dermatitis (AD), yet our understanding of them is limited. From a cohort of very young AD children (1 to 3 years old), sensitized to Dermatophagoides pteronyssinus allergens (Der p), we conducted culturomic analysis of skin microbiota, cutaneous transcript profiling and quantification of anti-Der p CD4+ T cells. This showed that the presence of S. aureus in inflamed skin of AD patients was associated with a high IgE response, increased expression of inflammatory and Th2/Th22 transcripts and the prevalence of a peripheral Th2 anti-Der p response. Monocyte-derived dendritic cells (moDC) exposed to the S. aureus and S. epidermidis secretomes were found to release pro-inflammatory IFN-γ and anti-inflammatory IL-10, respectively. Allogeneic moDC exposed to the S. aureus secretome also induced the proliferation of CD4+ T cells and this effect was counteracted by concurrent exposure to the S. epidermidis secretome. In addition, whereas the S. epidermidis secretome promoted the activity of regulatory T cells (Treg) in suppressing the proliferation of conventional CD4+ T cells, the Treg lost this ability in the presence of the S. aureus secretome. We therefore conclude that S. aureus may cause and promote inflammation in the skin of AD children through concomitant Th2 activation and the silencing of resident Treg cells. Commensals such as S. epidermidis may counteract these effects by inducing the release of IL-10 by skin dendritic cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141067PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624846PMC
June 2016

Polidocanol inhibits cowhage - but not histamine-induced itch in humans.

Exp Dermatol 2014 Dec;23(12):922-3

Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Polidocanol is a local anaesthetic and antipruritic compound that is used in the treatment of itching skin conditions such as eczema. Its mechanisms of action are largely ill defined. This study has compared the antipruritic efficacy of topical polidocanol in histamine-induced itch and a histamine-independent, cowhage-induced model of pruritus. Polidocanol (3%) or vehicle was applied topically under occlusion for 1 h to the forearms of 45 healthy volunteers before itch was provoked by rubbing in 40-45 spicules of cowhage or skin prick testing with 10 mg/ml histamine. Itch was recorded at 1-min intervals for 30 min on a 100-mm visual analogue scale. Polidocanol significantly reduced the area under the curve for cowhage-induced itch by 58% (P < 0.05), but had no significant effect on histamine-induced itch. This result underlines the importance of histamine-independent itch models in the development of topical antipruritic agents.
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http://dx.doi.org/10.1111/exd.12555DOI Listing
December 2014

Cathepsin S, a new pruritus biomarker in clinical dandruff/seborrhoeic dermatitis evaluation.

Exp Dermatol 2014 Apr;23(4):274-5

Pierre Fabre Dermo-Cosmétique, Toulouse, France.

Dandruff/seborrhoeic dermatitis (D/SD) is characterized by Malassezia colonization, impaired barrier function with subsequent inflammation, resulting in dandruff and itching. Histamine is one of the biomarkers of pruritus now widely used in treatment efficacy trials. The exact mechanism leading to histamine release and pruritus is not yet clear. However, it could involve cathepsin S, an activator of proteinase-activated receptor 2 (PAR2). The purpose of this study was to evaluate the levels of cathepsin S, PAR2 and histamine in patients with D/SD compared with healthy subjects through non-invasive sampling of the scalp and to correlate those markers with D/SD clinical parameters. A significant increase in the three biological markers was observed in the D/SD group versus healthy subjects, and those markers were correlated with clinical parameters. In conclusion, cathepsin S could be a potential marker of pruritus in D/SD and could help assessing the effect of treatments.
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http://dx.doi.org/10.1111/exd.12357DOI Listing
April 2014

Clinical and biochemical assessment of maintenance treatment in chronic recurrent seborrheic dermatitis: randomized controlled study.

Dermatol Ther (Heidelb) 2014 Jun 19;4(1):43-59. Epub 2014 Mar 19.

Service Exploration Clinique, Hôtel Dieu, Toulouse, France,

Introduction: Few studies have investigated the long-term effects of a maintenance regimen in the prevention of relapses in scalp seborrheic dermatitis (SD), in particular following biomarker changes.

Materials And Methods: A new shampoo containing beta-glycyrrhetinic acid (18βGA) in addition to cyclopiroxolamine (CPO) and zinc pyrithione (ZP) was tested in 67 subjects suffering from SD with moderate to severe erythema and itching in a biphasic study. After a first common intensive treatment phase (investigational product thrice a week × 2 weeks), subjects randomly received the investigational product once a week × 8 weeks (maintenance) or a neutral shampoo (discontinuation) in a comparative, parallel group maintenance phase. Efficacy was assessed clinically (overall clinical dandruff score, erythema, overall efficacy, self-evaluation), biochemically and microbiologically by quantitative polymerase chain reaction (qPCR), high performance liquid chromatography (HPLC) or enzyme-linked immunoabsorbent assay (ELISA) analysis of scale samples (Malassezia species (restricta and globosa), cohesion proteins (plakoglobins), inflammation (Interleukin (IL)-8, IL-1RA/IL-1α) and pruritus (histamine, cathepsin S) markers).

Results: During the intensive treatment phase, SD improved significantly (p < 0.0001) with a decrease in clinical signs as well as Malassezia species, cohesion proteins, inflammation and pruritus markers. During the maintenance phase, the improvement persisted in the 'maintenance' group only, with a significant intergroup difference. A consistently positive relationship was found between dandruff, itching, erythema and Malassezia populations, histamine levels and IL-1RA/IL-1α ratio.

Conclusion: The effectiveness of this maintenance regimen was objectively demonstrated at the clinical, biochemical and microbiological level. Correlations between clinical signs and biomarkers could provide clues to explain the resolution of SD and confirm the interest of biomarkers for SD treatment assessment.
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http://dx.doi.org/10.1007/s13555-014-0047-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065270PMC
June 2014

Association between collagen production and mechanical stretching in dermal extracellular matrix: in vivo effect of cross-linked hyaluronic acid filler. A randomised, placebo-controlled study.

J Dermatol Sci 2013 Mar 5;69(3):187-94. Epub 2013 Jan 5.

Centre de Recherche sur la Peau Pierre Fabre, Hôtel Dieu, Toulouse, France.

Background: The effects of hyaluronic acid (HA) injection on tissue collagen anabolism are suggested to be related to the induction of mechanical stress, causing biochemical changes in skin physiology.

Objectives: To ascertain the association between dermal mechanics modulated by a hyaluronic acid-based filler effect and metabolism.

Methods: Sixty females were randomised to receive a 0.5mL injection of HA gel or isotonic sodium chloride (control) in the arm. Skin biopsies were taken at baseline and after 1, 3 and 6 months. Protein and gene expression of procollagen, matrix metalloproteinases (MMP) and MMP tissue inhibitors (TIMP1) were measured blind by ELISA and qPCR, respectively. Injected volumes were measured by high-frequency ultrasound and radiofrequency analysis. Skin layer effects of injections were analysed by finite element digital modelling.

Results: One month after injection, the filler induced an increase in procollagen (p=0.0016) and TIMP-1 (p=0.0485) levels and relative gene expression of procollagen III and I isoforms compared with the controls. After 3 months, procollagen levels remained greater than in the controls (p=0.0005), whereas procollagen expression and TIMP-1 and MMP content were no longer different. Forty-three percent of the injected filler volume was found at 1 month, 26% after 3 months and 20% after 6 months.

Limitations: The ultrasound imaging technique limited the scope of the investigation and precluded an evaluation of the action of the filler at the hypodermic level.

Conclusions: Integrating both mechanical and biological aspects, our results suggest that mechanical stress generated by cross-linked HA plays a role in dermal cell biochemical response.
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http://dx.doi.org/10.1016/j.jdermsci.2012.12.006DOI Listing
March 2013

Quantification of Demodex folliculorum by PCR in rosacea and its relationship to skin innate immune activation.

Exp Dermatol 2012 Dec;21(12):906-10

Pôle Recherche, Exploration, Développement Clinique et Vigilances, Pierre Fabre Dermo-Cosmétique, Toulouse, France.

The aim of this study is to quantify D. folliculorum colonisation in rosacea subtypes and age-matched controls and to determine the relationship between D. folliculorum load, rosacea subtype and skin innate immune system activation markers. We set up a multicentre, cross-sectional, prospective study in which 98 adults were included: 50 with facial rosacea, including 18 with erythematotelangiectatic rosacea (ETR), and 32 with papulopustular rosacea (PPR) and 48 age- and sex-matched healthy volunteers. Non-invasive facial samples were taken to quantify D. folliculorum infestation by quantitative PCR and evaluate inflammatory and immune markers. Analysis of the skin samples show that D. folliculorum was detected more frequently in rosacea patients than age-matched controls (96% vs 74%, P < 0.01). D. folliculorum density was 5.7 times higher in rosacea patients than in healthy volunteers. Skin sample analysis showed a higher expression of genes encoding pro-inflammatory cytokines (Il-8, Il-1b, TNF-a) and inflammasome-related genes (NALP-3 and CASP-1) in rosacea, especially PPR. Overexpression of LL-37 and VEGF, as well as CD45RO, MPO and CD163, was observed, indicating broad immune system activation in patients with rosacea. In conclusion, D. folliculorum density is highly increased in patients with rosacea, irrespective of rosacea subtype. There appears to be an inverse relationship between D. folliculorum density and inflammation markers in the skin of rosacea patients, with clear differences between rosacea subtypes.
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http://dx.doi.org/10.1111/exd.12030DOI Listing
December 2012

Exploration of the global antioxidant capacity of the stratum corneum by cyclic voltammetry.

J Pharm Biomed Anal 2006 Jan 30;40(1):162-7. Epub 2005 Aug 30.

Laboratoire de Génie Chimique, UMR CNRS 5503, Université Paul Sabatier - ToulouseIII, 118 route de Narbonne, 31062 Toulouse, France.

Cyclic voltammetry is proposed as a new method for evaluating the antioxidant capacity of skin based on the reducing properties of low molecular weight antioxidants (LMWA). Experiments were performed simply by recording the anodic current at 0.9 V/SCE of a platinum microelectrode placed directly on the epidermis surface without any gel or water. This method ensured a direct, rapid (less than 1 min), reliable (accuracy 12%) and non-invasive measurement of the global antioxidant capacity of the stratum corneum with a high spatiotemporal resolution. At the same time, the pH of the skin surface was determined by recording the cathodic current at 0 V/SCE. Based on an exploratory study involving nine volunteer subjects, the evolution of the amperometric response of the microelectrode with time revealed a periodic modification of the redox properties.
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http://dx.doi.org/10.1016/j.jpba.2005.05.035DOI Listing
January 2006

Slow internal release of bioactive compounds under the effect of skin enzymes.

J Invest Dermatol 2005 Aug;125(2):270-7

Institut de Recherche Pierre Fabre, Toulouse Cedex, France.

A new strategy for the skin delivery of bioactive compounds has been developed, using enzymes involved in the maintenance of the epidermal barrier function and the enzymatic transformation of corresponding precursors. This new strategy has been tested with regard to two enzymatic activities of the skin barrier: extracellular glucosidase and esterase/lipase. An analysis of the requirements for the glycosidic bond hydrolysis of any glycoconjugate by beta-glucocerebrosidase indicates that the release of the moiety linked to the glucose unit is obtained as long as the glycosidic bond being broken is not hindered, and as long as the leaving group property of the released moiety is good enough. This strategy was first applied to the release of the antioxidant delta-tocopherol. It was then extended to retinoic acid by introducing a spacer between the glucose unit and the bioactive moiety. This spacer was either a good leaving group such as hydroquinone, or a structure akin to a ceramide, namely glycerol. In these conditions, beta-glucocerebrosidase releases the complex spacer-active compound that is cleaved by an esterase. One of the advantages of this strategy lies in the slow release of the bioactive compound, extending in time its effect and most likely its tolerance, as is the case for retinoic acid.
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http://dx.doi.org/10.1111/j.0022-202X.2005.23785.xDOI Listing
August 2005

Skin absorption and metabolism of a new vitamin E prodrug, delta-tocopherol-glucoside: in vitro evaluation in human skin models.

J Control Release 2004 Nov;100(2):221-31

Laboratoire de Pharmacocinétique Cutanée, Institut de Recherche Pierre Fabre, 31320 Vigoulet-Auzil, France.

The aim of this study was to investigate the cutaneous penetration and metabolism of the new vitamin E prodrug delta-tocopherol glucoside (delta-TG), as compared to those of common vitamin E acetate, in vitro, both in reconstituted human epidermis and in viable human skin. Better diffusion was observed with alpha-tocopherol acetate (alpha-TAc) than with delta-tocopherol glucoside in both skin models, at 0.1% and 0.05% in a myritol solution; however, no metabolism was detected with alpha-tocopherol acetate. In all conditions tested (two skin models, two concentrations, three test times, and compartmental analysis) the delta-tocopherol glucoside was metabolized into free tocopherol. In the reconstituted human epidermis, after 18 h, over 90% of the delta-tocopherol glucoside was bioconverted. In the viable human skin, the extent of metabolism was about 20%, with 0.12 and 0.10 microg/cm2 of delta-tocopherol glucoside in the stratum corneum and epidermis, respectively. After topical application, the delta-tocopherol glucoside had a considerable reservoir effect, associated with gradual delivery of free tocopherol. The use of this gluco-conjugated vitamin E at a low concentration shows the capability of the skin to metabolize the prodrug in a slow and prolonged manner, making this gluco-conjugated vitamin E an excellent candidate for continuous reinforcement of antioxidants in the skin.
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http://dx.doi.org/10.1016/j.jconrel.2004.08.012DOI Listing
November 2004

Human epidermis is a novel site of phospholipase B expression.

Biochem Biophys Res Commun 2002 Jul;295(2):362-9

Institut de recherche Pierre Fabre, CERPER/Hôtel Dieu Saint Jacques, F31052 Toulouse, France.

Phospholipase B (PLB) is an enzyme that displays both phospholipase A(2) and lysophospholipase activities. Analysis of human epidermis homogenates indicated the presence of a 97 kDa PLB protein, as well as a phospholipase A(2) activity, both being enriched in the soluble fraction. Immunolabelling and in situ hybridization experiments showed that this enzyme is expressed in the different layers of epidermis with an accumulation at the dermo-epidermis junction. RT-PCR data indicated that PLB is specifically expressed in natural and reconstructed epidermis. By 3'-RACE-PCR and screening of human genome databases, we obtained a 3600 bp cDNA coding for human PLB highly homologous to already described intestinal brush border PLBs. These data led us to conclude that the soluble PLB corresponds to a proteolytic cleavage of the membrane anchored protein. Altogether, our results provide the first characterization of human PLB which should play an important role in epidermal barrier function.
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http://dx.doi.org/10.1016/s0006-291x(02)00657-5DOI Listing
July 2002
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