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Quantitative systems pharmacology (QSP) is a novel approach to gain insights into the pathophysiology of a disease, optimize the efficacy of therapies and reduce the risk for new drug development. Together with Grünenthal, Rosa developed a QSP model, a Psoriasis PhysioPD Research Platform to mechanistically represent the physiology of a single chronic psoriatic plaque (including keratinocytes, immune cells, cytokines and chemokines and their regulation), drug PK and clinical outcomes (e.g., PASI score).
Psoriasis is the most common chronic autoimmune skin condition, impacting roughly 125 million people worldwide. The pathogenesis is not wholly understood, though an assumed complex interplay between environmental factors, immune dysregulation and genetic susceptibility. Data suggests that an environmental/pathogenic insult to the skin precipitates the activation of immune cells in the skin leading to a dysregulated pro-inflammatory response. This response triggers secretion of IL-12 and IL-23, causing migration and differentiation of Th17 and Th1 cells.
Atopic dermatitis (AD) is a chronic inflammatory skin disease where >90% of AD patients exhibit Staphylococcus aureus (SA) colonization of their lesional skin. The density of SA colonization has been correlated with both severity of AD lesions and the degree of cutaneous inflammation. A filaggrin-defect atopic dermatitis mouse model (FLGft/ft mice) has been used previously to correlate the depth of SA skin penetration with upregulation of IL-4, IL-13 and other cytokines. Using this model where mice are first sensitized by ovalbumin and then exposed to 1 x 106 colony forming units (CFU) SA, a pilot study was conducted to identify the time course of peak cytokines levels (48 hrs) after cutaneous infection with SA and determine the optimal, treatment window (initiate dosing at 24 hrs).
Retinoids have a dominant role in topical acne therapy and to date, only RARβ and RARγ dual agonists have reached the market. Given the tissue distribution of RAR isoforms, it was hypothesized that developing RARγ –selective agonists could yield a new generation of topical acne treatments that would increase safety margins while maintaining the robust efficacy of previous drugs. Structural knowledge derived from the X-Ray structure of known γ–selective CD437, revealed an unprecedented and isotype specific pocket in the RARγ ligand binding domain and enabled the optimization of a novel triaryl series of agonists which ultimately led to the discovery of Trifarotene.
First- and third-generation retinoids even though efficacious in acne, lack full selectivity for RARγ expressed in the epidermis and infundibulum. We describe the in vitro metabolism and the pharmacology of the novel retinoid trifarotene. Trifarotene is a selective RARγ agonist with >20-fold selectivity over RARa and RARβ. Trifarotene is active and stable in keratinocytes but rapidly metabolized by human hepatic microsomes, predicting improved safety. In vivo, trifarotene 0.01% applied topically is highly comedolytic and has antiinflammatory and antipigmenting properties.
Acute Generalized Exanthematous Pustulosis (AGEP) is a severe cutaneous adverse drug reaction characterized by an acute onset of sterile pustules on an erythematous background, fever and peripheral blood neutrophilia. Even though it is hypothesized that the massive neutrophilic infiltration seen in skin lesions is mediated by memory T cells via the production of IL-8, little is known about the early pathophysiology of AGEP. In our study, we could identify IL-36 as a possible key player in AGEP pathogenesis.
Skin is a complex multi-layered organ in which structure and cellular composition of each layer reflect its functional specialization. Both immune and stromal cells in superficial layers of the skin, epidermis and dermis, have been extensively studied. However, deeper layers of the skin - the hypodermis - remain largely unexplored. We used single-cell RNA-sequencing (scRNA-seq) to establish comparative maps of the cellular landscape of hypodermis and dermis. Ablation of myeloid subsets in Ccr2-KO mice and colony stimulating factor 1 (Csf1)-op/wt mice resulted in prominent changes in extracellular matrix (ECM)-associated genes in hypodermal fibroblasts at the single cell level.
Ex vivo skin culture is used as a proxy for understanding cutaneous biology. A potential confounding factor of this method is culture-induced expression of cytokines and chemokines. These studies were designed to investigate mechanism(s) of skin culture-induced cytokine and chemokine expression. Time course studies of ex vivo-cultured mouse tail skin were performed, and transcript for Il1a, Il6, Tnf, Tslp, Csf2 and Cxcl1 were measured by quantitative PCR. Compared to freshly isolated skin, Il6, Csf2, and Cxcl1 were significantly increased within 4 hours of culture; in contrast, Il1a, Tnf and Tslp increased later (e.g.
Aspergillus species, a common saprophytic mold, seldom acts as a pathogen in immunocompetent hosts, and primary cutaneous involvement is even less. Herein, we report a patient of primary cutaneous aspergillosis harboring CARD9 mutations. The 45-year-old patient presented with a 37-year history of skin lesions on the face. The lesion was a soy-sized rash on his left eyelid at the age of 8, which slowly enlarged and progressed during the past 3 years. Physical examination revealed erythematous plaques with clear border on his face and nose.
Background: Single Locus Sequence Typing (SLST) marker gene sequencing has recently been described for determining down-to strain level identification of specific bacteria within a microbiome, such as for human skin. SLST appears to fill a niche between 16S and shotgun metagenomics, offering strain level resolution. Materials & Methods: On a human cohort of healthy volunteers, and patients with atopic dermatitis (AD) lesions, we applied and validated the SLST method for high-resolution sequencing-based Staphylococcus profiling on skin.
Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are present on resident skin cells. Activation of TRP channels has been shown to contribute to cutaneous inflammation. Our aim was to investigate the role of TRPA1 and TRPV1 in imiquimod (IMQ)-induced psoriasiform dermatitis. Aldara (5% IMQ) cream was applied using Finn chambers on TRPA1-/-, TRPV1-/- and TRPA1/V1 KO and WT mice. Skin infiltration, blood perfusion and skin scaling was daily determined. Expression of IL-1β, TNF-α, IL-17, IL-22 and IL-23 mRNA were measured by RT-PCR.
The 2014-2016 Ebola virus (EBOV) outbreak in West Africa provided evidence for skin being a route of human to human viral transmission. Yet, the skin cell populations that are susceptible to EBOV infection and support EBOV replication are unknown. To investigate what skin cell types support EBOV, we utilized a human organ culture model where skin explants are cultured on nylon inserts at the air-liquid interface and a BSL2 replication competent recombinant virus, EBOV GP-rVSV. Exposure to 102, 104 or 106 pfu resulted in a dose- and time-dependent increase in GFP fluorescence in intact skin and an associated increase in viral titer and viral genome using qRT-PCR, thus confirming viral replication.
Aldara-induced psoriasiform dermatitis has several advantages compared to previous models such as quick and reproducible skin response, and it is relatively inexpensive. Otherwise this model has several limitations: overuse of the Aldara cream and its ingestion are the most problematic as it can cause severe systemic inflammation proven by splenomegaly, worsened general condition and untimely death. Our aim was to refine this model to reduce these systemic effects. In the original protocol (OP) group 62.5 mg Aldara cream (5% IMQ) or vaseline (as control) was applied on the shaved back skin of C57BL/6 mice on each day of experiment.
Keratinocytes are important gatekeepers of our body, forming a complex barrier. They distinguish between friendly microbes and harmful invaders and initiate effective immune responses if necessary. Tight regulation of these innate immune events are crucial, as they may quickly become deleterious, if not properly controlled. We aimed to analyze the regulation of innate immune reactions of keratinocytes initiated upon the recognition of Cutibacterium acnes (C. acnes) bacterium. We identified TNIP1 as a factor exhibiting negative regulatory effects on C.
The microbiota colonizes all barrier sites where it is known to dramatically influence local immunity. We set out to address the question of whether the microbiota also promotes crosstalk between barrier tissues. To address this question, we monocolonized germ-free with the gut-resident bacteria, segmented filamentous bacteria (SFB) that is known to promote type 17 immune responses. We found that in addition of classical T cells, SFB leads to accumulation of IL17+Vγ6+ gd T-cells both within the gut and systemically.
The pathogenesis of psoriasis, actually, is not fully understood, long-time clinical observation substantiated microbial infections intimate relationship with onset, in particular, an association between streptococcal throat infection Interestingly, worsening is exclusively associated with throat infection by beta haemolytic streptococci expressing M protein, that cross-reacts with human epidermal keratins and is targeted by T cells from psoriasis patients. We performed evaluation of Streptococcal infection: throat swabs were positive in 61 patients (pt) (21,63%) and 22 HC (10,23 %).
Coagulase-negative Staphylococcus (CoNS) have been shown to reside on human skin and are now known participate in immune defense against Staphylococcus aureus by producing antimicrobial peptides (AMPs) (Sci. Transl. Med. 9, eaah4680, 2017). These anti-Staph aureus bacteria are frequent on normal skin, but are rare on the skin of patients with atopic dermatitis. In this study, to further understand how the commensal CoNS community shapes the skin microbiome, we characterized the antimicrobial activity of commensal CoNS clones against various other pathogens associated with skin infections.
miR-10a has been shown to regulate proliferation, migration and inflammatory responses in various cell types. Here we studied miR-10a expression and functions in keratinocytes (KCs) and atopic dermatitis (AD). miR-10a was detected to be upregulated in human primary KCs and skin of AD patients with RT-qPCR and in situ hybridization. miR-10a expression was higher in proliferating KCs and decreased during in vitro reconstruction of the epidermis. The transfection of miR-10a into KCs downregulated the previously characterized miR-10a direct target MAP3K7 and NF-κB-influenced chemokines IL-8 and CCL5 both in unstimulated KCs and in cells stimulated with IL-1β.
Malaria begins when the Anopheles mosquito deposits motile Plasmodium sporozoites into the dermis, as it salivates and probes the skin in search of a blood meal. From the dermal inoculation site, sporozoites must travel and invade blood vessels to reach the liver and establish systemic infection. Mosquito saliva has been shown to have both pro- and anti-infective effects on Plasmodium. It remains unclear, however, how specific salivary proteins affect sporozoite behavior in the skin. We hypothesize that an Anopheles gambiae mosquito salivary protein with homology to the human gamma interferon inducible thiol reductase (GILT) is a key regulator in the pathogenesis of mammalian malaria transmission in the skin.
Atopic Dermatitis (AD) is characterized by an increased susceptibility to skin infections. Staphylococcus aureus (SA) is reported to dominate in AD lesions, and the presence of SA is felt to exacerbate eczema. Bleach baths have become a commonplace recommendation by dermatologists. Yet multiple studies have demonstrated conflicting efficacy of bleach baths in reducing skin colonization by S. aureus in AD patients, and a recent systematic review of all studies evaluating the efficacy of bleach baths for AD showed no difference in the SA density in patients treated with bleach versus water baths.