EGFR inhibitors erlotinib and lapatinib ameliorate epidermal blistering in pemphigus vulgaris in a non-linear, V-shaped relationship

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Toll-like receptor-ligand induced thymic stromal lymphopoietin expression in primary equine keratinocytes.

BACKGROUND Thymic stromal lymphopoietin (TSLP) plays a key role in the development of allergic inflammation. Little is known about possible triggers of equine TSLP expression. HYPOTHESIS/OBJECTIVES To investigate TSLP expression in equine insect bite hypersensitivity (IBH) skin lesions. The capacity of TLR 1-8 ligands (L) and of atopic cytokine milieu as potential triggers of TSLP and of interleukin (IL)-6 as a downstream effector molecule of TLR signalling, were examined in primary equine keratinocyte cultures. ANIMALS Lesional skin from IBH-affected and healthy skin from control-horses (n = 9 each group) was sampled. METHODS AND MATERIALS Keratinocyte cultures were established from six healthy horses and stimulated with TLR 1-8-L, and with IL-4 and tumor necrosis factor-α, to mimic an atopic inflammation cytokine milieu. TSLP and IL-6 gene expression was assessed by quantitative real-time PCR. RESULTS Expression of TSLP was significantly greater in IBH lesions compared to healthy skin. TLR 1-8-L significantly upregulated TSLP expression in keratinocytes. The strongest upregulation was induced by TLR 1/2-L and TLR 3-L. Combination of atopic cytokine milieu and TLR 1/2-L or TLR 3-L further increased TSLP expression. TLR-L 1-5 stimulation significantly upregulated IL-6 expression. CONCLUSIONS AND CLINICAL IMPORTANCE The data herein suggest that the upregulation of TSLP expression in lesional skin of IBH-affected horses might play a role in IBH development. Moreover, TSLP expression is induced by TLR-L, in particular by TLR 1/2-L and TLR 3-L, and is further increased by atopic cytokine milieu, indicating a mechanism for TSLP-mediated exacerbation of IBH

A Desmosomal Cadherin Controls Multipotent Hair Follicle Stem Cell Quiescence and Orchestrates Regeneration Through Adhesion Signaling

Stem cells (SCs) are critical to maintain tissue homeostasis. However, it is currently not known whether signaling through cell junctions protects quiescent epithelial SC reservoirs from depletion during disease-inflicted damage. Using the autoimmune model disease pemphigus vulgaris (PV), this study reveals an unprecedented role for a desmosomal cadherin in governing SC quiescence and regeneration through adhesion signaling in the multipotent mouse hair follicle compartment known as the bulge. Autoantibody-mediated, mechanical uncoupling of desmoglein (Dsg) 3 transadhesion activates quiescent bulge SC which lose their multipotency and stemness, become actively cycling, and finally delaminate from their epithelial niche. This then initiates a self-organized regenerative program which restores Dsg3 function and bulge morphology including SC quiescence and multipotency. These profound changes are triggered by the sole loss of functional Dsg3, resemble major signaling events in Dsg3−/− mice, and are driven by SC-relevant EGFR activation and Wnt modulation requiring longitudinal repression of Hedgehog signaling

An Intronic MBTPS2 Variant Results in a Splicing Defect in Horses with Brindle Coat Texture

We investigated a family of horses exhibiting irregular vertical stripes in their hair coat texture along the neck, back, hindquarters, and upper legs. This phenotype is termed "brindle" by horse breeders. We propose the term "brindle 1 (BR1)" for this specific form of brindle. In some BR1 horses the stripes were also differentially pigmented. Pedigree analyses were suggestive of a monogenic X-chromosomal semi-dominant mode of inheritance. Haplotype analyses identified a 5 Mb candidate region on chromosome X. Whole genome sequencing of 4 BR1 and 60 non-brindle horses identified 61 private variants in the critical interval, none of them located in an exon of an annotated gene. However, one of the private variants was close to an exon/intron boundary in intron 10 of the MBPTS2 gene encoding the membrane bound transcription factor peptidase, site 2 (c.1437+4T>C). Different coding variants in this gene lead to three related genodermatoses in human patients. We therefore analyzed MBPTS2 transcripts in skin and identified an aberrant transcript in a BR1 horse, which lacked the entire exon 10 and parts of exon 11. The MBPTS2:c1437+4T>C variant showed perfect co-segregation with the brindle phenotype in the investigated family and was absent from 457 control horses of diverse breeds. Altogether, our genetic data and the previous knowledge on MBTPS2 function in the skin suggest that the identified MBTPS2 intronic variant leads to partial exon skipping and causes the BR1 phenotype in horses

A Mutation in the SUV39H2 Gene in Labrador Retrievers with Hereditary Nasal Parakeratosis (HNPK) Provides Insights into the Epigenetics of Keratinocyte Differentiation.

Peer reviewe

Developmentally Controlled Farnesylation Modulates AtNAP1;1 Function in Cell Proliferation and Cell Expansion during Arabidopsis Leaf Development

In multicellular organisms, organogenesis requires tight control and coordination of cell proliferation, cell expansion, and cell differentiation. We have identified Arabidopsis (Arabidopsis thaliana) nucleosome assembly protein 1 (AtNAP1;1) as a component of a regulatory mechanism that connects cell proliferation to cell growth and expansion during Arabidopsis leaf development. Molecular, biochemical, and kinetic studies of AtNAP1;1 gain- or loss-of-function mutants indicate that AtNAP1;1 promotes cell proliferation or cell expansion in a developmental context and as a function of the farnesylation status of the protein. AtNAP1;1 was farnesylated and localized to the nucleus during the cell proliferation phase of leaf development when it promotes cell division. Later in leaf development, nonfarnesylated AtNAP1;1 accumulates in the cytoplasm when it promotes cell expansion. Ectopic expression of nonfarnesylated AtNAP1;1, which localized to the cytoplasm, disrupts this developmental program by promoting unscheduled cell expansion during the proliferation phase

A new light on an old disease: adhesion signaling in pemphigus vulgaris.

Disruption of desmosomal cadherin adhesion leads to the activation of intracellular signaling pathways that are responsible for blister formation in pemphigus vulgaris (PV). Recent studies corroborate the implication of the p38 mitogen-activated protein kinase in PV blistering via its downstream effector mitogen-activated protein kinase activated protein kinase 2. These insights highlight the key role of cadherins in tissue homeostasis and are expected to change pemphigus management

Farnesylation Directs AtIPT3 Subcellular Localization and Modulates Cytokinin Biosynthesis in Arabidopsis1[OA]

Cytokinins regulate cell division and differentiation as well as a number of other processes implicated in plant development. The first step of cytokinin biosynthesis in Arabidopsis (Arabidopsis thaliana) is catalyzed by adenosine phosphate-isopentenyltransferases (AtIPT). The enzymes are localized in plastids or the cytoplasm where they utilize the intermediate dimethylallyl-diphosphate from the methylerythritolphosphate or mevalonic acid pathways. However, the regulatory mechanisms linking AtIPT activity and cytokinin biosynthesis with cytokinin homeostasis and isoprenoid synthesis are not well understood. Here, we demonstrate that expression of AtIPT3, one member of the adenosine AtIPT protein family in Arabidopsis, increased the production of specific isopentenyl-type cytokinins. Moreover, AtIPT3 is a substrate of the protein farnesyl transferase, and AtIPT3 farnesylation directed the localization of the protein in the nucleus/cytoplasm, whereas the nonfarnesylated protein was located in the plastids. AtIPT3 gain-of-function mutant analysis indicated that the different subcellular localization of the farnesylated protein and the nonfarnesylated protein was closely correlated with either isopentenyl-type or zeatin-type cytokinin biosynthesis. In addition, mutation of the farnesyl acceptor cysteine-333 of AtIPT3 abolishes cytokinin production, suggesting that cysteine-333 has a dual and essential role for AtIPT3 farnesylation and catalytic activity

SUV39H2 epigenetic silencing controls fate conversion of epidermal stem and progenitor cells.

Epigenetic histone trimethylation on lysine 9 (H3K9me3) represents a major molecular signal for genome stability and gene silencing conserved from worms to man. However, the functional role of the H3K9 trimethylases SUV39H1/2 in mammalian tissue homeostasis remains largely unknown. Here, we use a spontaneous dog model with monogenic inheritance of a recessive SUV39H2 loss-of-function variant and impaired differentiation in the epidermis, a self-renewing tissue fueled by stem and progenitor cell proliferation and differentiation. Our results demonstrate that SUV39H2 maintains the stem and progenitor cell pool by restricting fate conversion through H3K9me3 repressive marks on gene promoters encoding components of the Wnt/p63/adhesion axis. When SUV39H2 function is lost, repression is relieved, and enhanced Wnt activity causes progenitor cells to prematurely exit the cell cycle, a process mimicked by pharmacological Wnt activation in primary canine, human, and mouse keratinocytes. As a consequence, the stem cell growth potential of cultured SUV39H2-deficient canine keratinocytes is exhausted while epidermal differentiation and genome stability are compromised. Collectively, our data identify SUV39H2 and potentially also SUV39H1 as major gatekeepers in the delicate balance of progenitor fate conversion through H3K9me3 rate-limiting road blocks in basal layer keratinocytes

Sécuriser

La sécurité reste au centre du débat public, à l'école et dans la société. Les textes présentés ici se situent non pas du côté de la violence telle qu'elle est exercée mais de celui du sentiment d'insécurité, tel qu'il est vécu et se placent délibérément dans la perspective des victimes éventuelles, en étudiant le vécu objectif