Glucocorticoid Receptor Signaling in Skin Barrier Function

Glucocorticoids (GCs) are steroid hormones that regulate the physiology of all tissues and mediate stress responses. Synthetic GCs are commonly prescribed to treat chronic inflammatory conditions including the prevalent skin diseases—psoriasis and atopic dermatitis. GCs act through the GC receptor (GR, NR3C1), a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. In skin, GC therapeutic efficacy is due to the antiproliferative and anti-inflammatory actions of GR; however, in the long term, these benefits are accompanied by adverse profiles including skin atrophy, increased fragility, dehydration, augmented susceptibility to infections, and delayed wound healing. While the therapeutic actions of GC treatments have been extensively studied, only more recently has the physiological role of GR been addressed in skin. In vivo and in vitro studies in mouse and man have revealed an important function for GR in skin homeostasis. In particular, the characterization of gain- or loss-of-function mouse models has demonstrated relevant roles for GR in skin pathophysiology. The actions of GR are context dependent, and in skin, it regulates different gene subsets and biological processes depending on developmental stage and physiological state. Finally, recent findings emphasize the relevance of local GC biosynthesis and appropriate GR expression in maintaining skin homeostasis

Epidermal inactivation of the glucocorticoid receptor triggers skin barrier defects and cutaneous inflammation.

9 páginas, 5 figuras. En material suplementario 7 figuras, 2 tablas.The glucocorticoid (GC) receptor (GR) mediates the effects of physiological and pharmacological GC ligands and has a major role in cutaneous pathophysiology. To dissect the epithelial versus mesenchymal contribution of GR in developing and adult skin, we generated mice with keratinocyte-restricted GR inactivation (GR epidermal knockout or GR(EKO) mice). Developing and early postnatal GR(EKO) mice exhibited impaired epidermal barrier formation, abnormal keratinocyte differentiation, hyperproliferation, and stratum corneum (SC) fragility. At birth, GR(EKO) epidermis showed altered levels of epidermal differentiation complex genes, proteases and protease inhibitors which participate in SC maintenance, and innate immunity genes. Many upregulated genes, including S100a8/a9 and Tslp, also have increased expression in inflammatory skin diseases. Infiltration of macrophages and degranulating mast cells were observed in newborn GR(EKO) skin, hallmarks of atopic dermatitis. In addition to increased extracellular signal-regulated kinase activation, GR(EKO) newborn and adult epidermis had increased levels of phosphorylated signal transducer and activator of transcription 3, a feature of psoriasis. Although adult GR(EKO) epidermis had a mild phenotype of increased proliferation, perturbation of skin homeostasis with detergent or phorbol ester triggered an exaggerated proliferative and hyperkeratotic response relative to wild type. Together, our results show that epidermal loss of GR provokes skin barrier defects and cutaneous inflammation.This work was supported by grant SAF2008-00540 and SAF2011-28115 of the Ministerio de Ciencia e Innovación/Economía y Competitividad from the Spanish Government and ACOMP2011/127 from Generalitat Valenciana. LMS holds a JAE-DOC contract partly supported by the EC and VL is a recipient of an FPI fellowship of MICINN (BES-2009-021944).Peer reviewe

Selective ablation of glucocorticoid receptor in mouse keratinocytes increases susceptibility to skin tumorigenesis.

9 páginas, 5 figuras. En material suplementario 5 figuras.We recently demonstrated that mice lacking the epidermal glucocorticoid (GC) receptor (GR) (GR epidermal knockout (GR(EKO)) mice) have developmental defects and sensitivity to epidermal challenge in adulthood. We examined the susceptibility of GR(EKO) mice to skin chemical carcinogenesis. GR(EKO) mice treated with a low dose of 12-dimethylbenz(a) anthracene (DMBA) followed by phorbol 12-myristate 13-acetate (PMA) promotion exhibited earlier papilloma formation with higher incidence and multiplicity relative to control littermates (CO). Augmented proliferation and inflammation and defective differentiation of GR(EKO) keratinocytes contributed to the phenotype, likely through increased AKT and STAT3 (signal transducer and activator of transcription 3) activities. GR(EKO) tumors exhibited signs of early malignization, including delocalized expression of laminin A, dermal invasion of keratin 5 (K5)-positive cells, K13 expression, and focal loss of E-cadherin. Cultured GR(EKO) keratinocytes were spindle like, with loss of E-cadherin and upregulation of smooth muscle actin (SMA) and Snail, suggesting partial epithelial-mesenchymal transition. A high DMBA dose followed by PMA promotion generated sebaceous adenomas and melanocytic foci in GR(EKO) and CO. Importantly, the number, growth kinetics, and extent of both tumor types increased in GR(EKO) mice, suggesting that in addition to regulating tumorigenesis from epidermal lineages, GR in keratinocytes is important for cross-talk with other skin cells. Altogether, our data reinforce the importance of GR in the pathogenesis of skin cancer.This work was supported by grant SAF2011-28115 of the Ministerio de Economía y Competitividad from the Spanish government. VL holds a fellowship from the MICINN (BES-2009-021944).Peer reviewe

Epidermal mineralocorticoid receptor plays beneficial and adverse effects in skin and mediates glucocorticoid responses

10 páginas, 6 figuras. Contiene material suplementarioGlucocorticoids (GCs) regulate skin homeostasis and combat cutaneous inflammatory diseases; however, adverse effects of chronic GC treatments limit their therapeutic use. GCs bind and activate the GC receptor and the mineralocorticoid receptor (MR), transcription factors that recognize identical hormone responsive elements. Whether epidermal MR mediates beneficial or deleterious GC effects is of great interest for improving GC-based skin therapies. MR epidermal knockout mice exhibited increased keratinocyte proliferation and differentiation and showed resistance to GC-induced epidermal thinning. However, crucially, loss of epidermal MR rendered mice more sensitive to inflammatory stimuli and skin damage. MR epidermal knockout mice showed increased susceptibility to phorbol 12-myristate 13-acetate-induced inflammation with higher cytokine induction. Likewise, cultured MR epidermal knockout keratinocytes had increased phorbol 12-myristate 13-acetate-induced NF-κB activation, highlighting an anti-inflammatory function for MR. GC-induced transcription was reduced in MR epidermal knockout keratinocytes, at least partially due to decreased recruitment of GC receptor to hormone responsive element-containing sequences. Our results support a role for epidermal MR in adult skin homeostasis and demonstrate nonredundant roles for MR and GC receptor in mediating GC actions.This work was supported by grant SAF2011-28115 and SAF2014-59474-R (MINECO, Spanish Government). JB and EC are recipients of FPI (BES-2012-0578) and FPU (AP201-06094) fellowships of MINECO, respectively. We thank COST ADMIRE BM- 1301 and NURCAMEIN (SAF2015-71878-REDT) for support for dissemination.Peer reviewe

The mineralocorticoid receptor plays a transient role in mouse skin development

3 páginas, 2 figuras. Contiene material suplemenarioGlucocorticoid (GC) hormones can bind two structurally and functionally related steroid receptors: the GC Receptor (GR or Nr3c1) and the mineralocorticoid receptor (MR or Nr3c2), which recognize the same DNA response elements and act as ligand-dependent transcription factors. While the crucial role of GR for skin homeostasis has been widely characterized, the exact role of MR in this tissue deserves further study. We assessed NR3C2 expression in developing and adult WT mouse skin and found a transient peak at embryonic day (E)16.5, which along with low levels of HSD11B2, the enzyme inactivating GCs, supports a role for GC-MR complexes in epidermal maturation. Consistent with this observation, MR-/- embryonic skin showed alterations in early epidermal differentiation that resolved postnatally. The lack of a more severe skin phenotype of MR-/- mice suggests functional compensation by GR in this tissue in the perinatal period.This work was supported by JSPS KAKENHI grant numbers 25870545 and 15K09772. Spanish Ministerio de Ciencia e Innovación. Grant Numbers: SAF2011-28115, SAF2014-59474-RPeer Reviewe

Establishing Diagnostic Skills in Novice Bilingual Clinicians: A Scaffolded Approach

This study sought to scaffold administration performance of a standardized bilingual screener to sufficient levels of accuracy for data collection using principles of Cognitive Load Theory by managing task complexity when training pre-service clinicians. Before training administration skills, two students were given copies of the manual for the Bilingual English Spanish Oral Screener (BESOS) and asked to administer the protocol independently. During the intervention phase, students were scaffolded through administration tasks of increasing complexity and given explicit instruction, which included tailored goals, modeling and feedback. Performance for four skills was assessed using a fidelity rubric and analyzed using visual analysis. Performance varied per skill but overall scores were higher during the intervention phases than during the baseline phase for both students. In addition, accuracy of performance maintained across client participants showing patterns of generalization. Although the data are limited, scaffolding training skills for pre-service clinicians appears supportive in training administration skills for bilingual tasks. The level of support may vary per skill and per language. Future research may seek to investigate other clinical skills and tasks

Multi-state open robust design applied to opportunistic data reveals dynamics of wide-ranging taxa: The sperm whale case.

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Boys, R. M., Oliveira, C., Perez-Jorgeo, S., Prieto, R., Steiner, L., & Silva, M. A. Multi-state open robust design applied to opportunistic data reveals dynamics of wide-ranging taxa: The sperm whale case. Ecosphere, 10(3), (2019):e02610, doi:10.1002/ecs2.2610.Capture–mark–recapture methods have been extensively used to estimate abundance, demography, and life history parameters of populations of several taxa. However, the high mobility of many species means that dedicated surveys are logistically complicated and expensive. Use of opportunistic data may be an alternative, if modeling takes into account the inevitable heterogeneity in capture probability from imperfect detection and incomplete sampling, which can produce significant bias in parameter estimates. Here, we compare covariate‐based open Jolly‐Seber models (POPAN) and multi‐state open robust design (MSORD) models to estimate demographic parameters of the sperm whale population summering in the Azores, from photo‐identification data collected opportunistically by whale‐watching operators and researchers. The structure of the MSORD also allows for extra information to be obtained, estimating temporary emigration and improving precision of estimated parameters. Estimates of survival from both POPAN and MSORD were high, constant, and very similar. The POPAN model, which partially accounted for heterogeneity in capture probabilities, estimated an unbiased super‐population of ~1470 whales, with annual abundance showing a positive trend from 351 individuals (95% CI: 234–526) in 2010 to 718 (95% CI: 477–1082) in 2015. In contrast, estimates of abundance from MSORD models that explicitly incorporated imperfect detection due to temporary emigration were less biased, more precise, and showed no trend over years, from 275 individuals (95% CI: 188–404) in 2014 to 367 (95% CI: 248–542) in 2012. The MSORD estimated short residence time and an even‐flow temporary emigration, meaning that the probability of whales emigrating from and immigrating to the area was equal. Our results illustrate how failure to account for transience and temporary emigration can lead to biased estimates and trends in abundance, compromising our ability to detect true population changes. MSORD models should improve inferences of population dynamics, especially when capture probability is low and highly variable, due to wide‐ranging behavior of individuals or to non‐standardized sampling. Therefore, these models should provide less biased estimates and more accurate assessments of uncertainty that can inform management and conservation measures.We acknowledge IFAW for providing photo‐identification data from the early period of the study (1987–1993), Biosphere Expeditions and clients of Whale Watch Azores for making data collection possible. We thank Sara Magalhães, Tiago Sá, João Medeiros, Yves Cuenot, Pablo Chevallard Navarro, and numerous volunteers that over the years helped with data collection and organization of the photo‐identification catalogue. We are deeply grateful to Gary White, Bill Kendall, Jim Hines, James Nichols, Paul Conn, and Olivier Gimenez for offering guidance and advice on CMR modeling. We thank Jonathan Gordon for his comments on an earlier version of the manuscript. We are thankful to the three anonymous reviewers for providing very helpful comments. This work was supported by Fundação para a Ciência e Tecnologia (FCT), Azores 2020 Operational Programme, and Fundo Regional da Ciência e Tecnologia (FRCT) through research projects FCT‐Exploratory project (IF/00943/2013/CP1199/CT0001), WATCH IT (Acores‐01‐0145‐FEDER‐000057), and MISTIC SEAS II (GA11.0661/2017/750679/SUB/ENV.C2) co‐funded by FEDER, COMPETE, QREN, POPH, ESF, Portuguese Ministry for Science and Education, and EU‐DG/ENV. The Azores 2020 Operational Programme is funded by the community structural funds ERDF and ESF. We also acknowledge funds provided by FCT to MARE, through the strategic project UID/MAR/04292/2013. Rebecca M Boys is supported by an Estagiar L scholarship, Cláudia Oliveira by a research assistant contract from WATCH IT and Mónica A Silva by an FCT‐Investigator contract (IF/00943/2013), and Rui Prieto by an FCT postdoctoral grant (SFRH/BPD/108007/2015). Mónica A Silva conceptualized the project, acquired funding, administered, and supervised the project. Lisa Steiner, Cláudia Oliveira, Rebecca M Boys, and Mónica A Silva involved in data curation. Rebecca M Boys, Mónica A Silva, Sergi Pérez‐Jorge, and Cláudia Oliveira involved in formal analysis, investigation, and methodology. Rebecca M Boys preparation and visualization of the data. Rebecca M Boys, Mónica A Silva, Sergi Pérez‐Jorge, Rui Prieto wrote the original draft of the manuscript. Rebecca M Boys, Mónica A Silva, Rui Prieto, Sergi Pérez‐Jorge, Cláudia Oliveira, and Lisa Steiner wrote, reviewed, and edited the manuscript

Glucocorticoid Resistance: Interference between the Glucocorticoid Receptor and the MAPK Signalling Pathways

Endogenous glucocorticoids (GCs) are steroid hormones that signal in virtually all cell types to modulate tissue homeostasis throughout life. Also, synthetic GC derivatives (pharmacological GCs) constitute the first-line treatment in many chronic inflammatory conditions with unquestionable therapeutic benefits despite the associated adverse effects. GC actions are principally mediated through the GC receptor (GR), a ligand-dependent transcription factor. Despite the ubiquitous expression of GR, imbalances in GC signalling affect tissues differently, and with variable degrees of severity through mechanisms that are not completely deciphered. Congenital or acquired GC hypersensitivity or resistance syndromes can impact responsiveness to endogenous or pharmacological GCs, causing disease or inadequate therapeutic outcomes, respectively. Acquired GC resistance is defined as loss of efficacy or desensitization over time, and arises as a consequence of chronic inflammation, affecting around 30% of GC-treated patients. It represents an important limitation in the management of chronic inflammatory diseases and cancer, and can be due to impairment of multiple mechanisms along the GC signalling pathway. Among them, activation of the mitogen-activated protein kinases (MAPKs) and/or alterations in expression of their regulators, the dual-specific phosphatases (DUSPs), have been identified as common mechanisms of GC resistance. While many of the anti-inflammatory actions of GCs rely on GR-mediated inhibition of MAPKs and/or induction of DUSPs, the GC anti-inflammatory capacity is decreased or lost in conditions of excessive MAPK activation, contributing to disease susceptibility in tissue- and disease- specific manners. Here, we discuss potential strategies to modulate GC responsiveness, with the dual goal of overcoming GC resistance and minimizing the onset and severity of unwanted adverse effects while maintaining therapeutic potential

Sex Differences in Clinical Features of Early, Treated Parkinson\u27s Disease

INTRODUCTION: To improve our understanding of sex differences in the clinical characteristics of Parkinson\u27s Disease, we sought to examine differences in the clinical features and disease severity of men and women with early treated Parkinson\u27s Disease (PD) enrolled in a large-scale clinical trial. METHODS: Analysis was performed of baseline data from the National Institutes of Health Exploratory Trials in Parkinson\u27s Disease (NET-PD) Long-term Study-1, a randomized, multi-center, double-blind, placebo-controlled study of 10 grams of oral creatine/day in individuals with early, treated PD. We compared mean age at symptom onset, age at PD diagnosis, and age at randomization between men and women using t-test statistics. Sex differences in clinical features were evaluated, including: symptoms at diagnosis (motor) and symptoms at randomization (motor, non-motor, and daily functioning). RESULTS: 1,741 participants were enrolled (62.5% male). No differences were detected in mean age at PD onset, age at PD diagnosis, age at randomization, motor symptoms, or daily functioning between men and women. Differences in non-motor symptoms were observed, with women demonstrating better performance compared to men on SCOPA-COG (Z = 5.064, p\u3c0.0001) and Symbol Digit Modality measures (Z = 5.221, p\u3c0.0001). CONCLUSIONS: Overall, men and women did not demonstrate differences in clinical motor features early in the course of PD. However, the differences observed in non-motor cognitive symptoms suggests further assessment of the influence of sex on non-motor symptoms in later stages of PD is warranted

From Your Nose to Your Toes: A Review of Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic‒Associated Pernio

Despite thousands of reported patients with pandemic-associated pernio, low rates of seroconversion and PCR positivity have defied causative linkage to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pernio in uninfected children is associated with monogenic disorders of excessive IFN-1 immunity, whereas severe COVID-19 pneumonia can result from insufficient IFN-1. Moreover, SARS-CoV-2 spike protein and robust IFN-1 response are seen in the skin of patients with pandemic-associated pernio, suggesting an excessive innate immune skin response to SARS-CoV-2. Understanding the pathophysiology of this phenomenon may elucidate the host mechanisms that drive a resilient immune response to SARS-CoV-2 and could produce relevant therapeutic targets