The immunological anatomy of the skin

Kabashima, Kenji; Honda, Tetsuya; Ginhoux, Florent; Egawa, Gyohei

doi:10.1038/s41577-018-0084-5

Cited by 395 publications

(365 citation statements)

References 99 publications

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“…To illustrate the utility of S^3, we apply it to generate a resource of single-cell transcriptional states spanning multiple inflammatory skin conditions. Skin represents the largest barrier tissue in the human body and is comprised of numerous specialized cell-types that help maintain both immunological and physical boundaries between our inner and outer worlds (Kabashima et al, 2019). The dermis and epidermis – the two primary compartments of human skin – play complementary roles in tissue structure and function ( Figure 2A ) (Kabashima et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Skin represents the largest barrier tissue in the human body and is comprised of numerous specialized cell-types that help maintain both immunological and physical boundaries between our inner and outer worlds (Kabashima et al, 2019). The dermis and epidermis – the two primary compartments of human skin – play complementary roles in tissue structure and function ( Figure 2A ) (Kabashima et al, 2019). The epidermis consists primarily of keratinized epithelial cells, which provide a physical barrier to the outside world; the dermis, meanwhile, provides structural support for the skin, with fibroblasts producing collagen and elastin fibrils along with the other components of the extracellular matrix.…”

Section: Introductionmentioning

confidence: 99%

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Highly Efficient, Massively-Parallel Single-Cell RNA-Seq Reveals Cellular States and Molecular Features of Human Skin Pathology

Tk¹,

Mh²,

Tm³

et al. 2019

Preprint

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1The development of high-throughput single-cell RNA-sequencing (scRNA-Seq) methodologies 2 has empowered the characterization of complex biological samples by dramatically increasing the 3 number of constituent cells that can be examined concurrently. Nevertheless, these approaches 4 typically recover substantially less information per-cell as compared to lower-throughput microtiter 5 plate-based strategies. To uncover critical phenotypic differences among cells and effectively link 6 scRNA-Seq observations to legacy datasets, reliable detection of phenotype-defining transcripts 7 -such as transcription factors, affinity receptors, and signaling molecules -by these methods is 8 essential. Here, we describe a substantially improved massively-parallel scRNA-Seq protocol we 9 term Seq-Well S^3 ("Second-Strand Synthesis") that increases the efficiency of transcript capture 10 and gene detection by up to 10-and 5-fold, respectively, relative to previous iterations, surpassing 11 best-in-class commercial analogs. We first characterized the performance of Seq-Well S^3 in cell 12 lines and PBMCs, and then examined five different inflammatory skin diseases, illustrative of 13 distinct types of inflammation, to explore the breadth of potential immune and parenchymal cell 14 states. Our work presents an essential methodological advance as well as a valuable resource 15 for studying the cellular and molecular features that inform human skin inflammation. 109Mann-Whitney U Test & Linear Regression; Figure 1B-C). To confirm that these overall 110 improvements were not driven by changes in the relative frequencies of different cell types 111 captured by each technology, we also examined each subset independently (Figure S2A-B). For 112 each cell type detected, we observed significant increases in the numbers of transcripts captured 113 and genes detected using S^3 for each pairwise comparison between techniques (P < 0.05, 114 Mann-Whitney U Test; CD4 + T cells, Seq-Well V1: 1,044 ± 62.3 UMIs/cell; 10x v2: 7,671 ± 103.9 115 UMIs/cell; Seq-Well S^3: 13,390 ± 253.4 UMIs/cell; Mean ± Standard Error of the Median (SEM); 116 Figure S2). Both Seq-Well S^3 and 10x v2 displayed increased sensitivity for transcripts and 117 genes relative to Seq-Well v1, but Seq-Well S^3 showed the greatest efficiency (defined as genes 118 recovered at matched read depth) to detect genes for each cell type (Figure 1D-E; Figure S2). 119We sought to further understand whether these improvements resulted in enhanced 120 detection of biologically relevant genes typically under-represented in high-throughput single-cell 121 sequencing libraries (Tabula Muris Consortium et al., 2018). Importantly, genes that were 122 differentially detected (i.e., higher in S^3) within each cell type include numerous transcription 123 factors, cytokines and cell-surface receptors (Figure 1D-E). For example, among CD4 + T cells, 124we observe significantly increased detection of cytokines (e.g., TGFB1 and TNF), surface 125 receptors (e.g., TGFBR and CCR4) and transcription fact...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Highly Efficient, Massively-Parallel Single-Cell RNA-Seq Reveals Cellular States and Molecular Features of Human Skin Pathology

Tk¹,

Mh²,

Tm³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition, it has been reported that Triadin regulates IP3 receptors in rat skeletal myoblasts (54), further investigations to show whether possible interaction between Trisk 95 and IP3R might take place in keratinocytes. 14 It is known that a high concentration of calcium induces differentiation markers such as loricrin, profilaggrin and involucrin in keratinocytes (55-57), and it has also been shown that keratinocytes located in different layers of the epidermis express different RYR receptors (58). The effects of the calcium level and of RYR expression upon the upregulation of Triadin under hyperglycaemia may therefore explain the poor wound healing observed in type I diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…Keratinocytes are the main cell type (≈90 %) constituting the epidermis (13,14), and with respect to their key roles in wound healing (15), they have been extensively studied, notably in cases of diabetes (16)(17)(18). Reports have demonstrated that impaired keratinocyte function can result in delayed wound healing, and that multiple physiological processes in keratinocytes, such as proliferation (19), migration (20), apoptosis (21) and differentiation (22), may be affected by a hyperglycaemic condition.…”

Section: Introductionmentioning

confidence: 99%

Trisk 95 as a Novel Skin Mirror for Normal and Diabetic Systemic Glucose Level

Ali

Reza-Rezvani

Motei

et al. 2019

Preprint

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Coping with diabetes requires frequent and even today mostly invasive blood glucose-based monitoring.Partly due to this invasive nature and the associated reduced skin wound healing and increased risk of infection, non-invasive glucose monitoring technologies would represent considerable progress. Edited keratinocytes may enable such a function.To address this hypothesis, we conducted a proteomic screen in the skin by making use of the experimental in vivo mouse model of type I diabetes alongside controls. We identified Trisk 95 as the only protein whose expression is induced in response to high blood glucose. A luciferase reporter assay demonstrated that induction of Trisk 95 expression occurs not only at the protein level but also transcriptionally. This induction was associated with a marked elevation in the Fluo-4 signal, suggesting a role for intracellular calcium changes in the signalling cascade. Strikingly, these changes lead concurrently to fragmentation of the mitochondria. As judged from the knockout findings, both the calcium flux and the mitochondrial phenotype were dependent on Trisk 95 function, since the phenotypes in question were abolished.The data demonstrate that the skin represents an organ that reacts robustly and thus mirrors changes in systemic blood glucose levels. The findings are also consistent with a channelling model of Trisk 95 that serves as an insulin-independent but glucose-responsive biomarker taking part in releasing calcium from the cellular stores in the skin. The skin cells may thus provide a novel mean for glucose monitoring when analysing changes in labelled Trisk 95 and calcium. By that, this study is the first proof of the concept of our registered patent (No. PCT FI2016/050917), which proposes the use of cells as biosensors for developing personalized health-monitoring devices.

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“…The subcutaneous tissue in which the bacteria were injected, also named hypodermis, is a well vascularized layer of adipose tissue and the most used skin layer for delivery of live attenuated virus vaccines. Although it is less drained by lymphatics than the actively surveyed dermis layer, injected particles succeed to reach LN via lymph to trigger adaptive immunity [19]. Because VTnF1 rapidly reached both LN and spleen (day 1), it must have gained access to both blood and lymphatic vessels, and this may result from a mechanical damage caused by injection.…”

Section: Vtnf1 Causes Little Side Effects and Disseminates Transientlmentioning

confidence: 99%

Subcutaneous vaccination with a live attenuated Yersinia pseudotuberculosis plague vaccine

Derbise

Guillas

Gerke

et al. 2019

Preprint

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A single oral inoculation to mice of the live attenuated Yersinia pseudotuberculosis VTnF1 strain producing an F1 pseudocapsule protects against bubonic and pneumonic plague.However oral vaccination can fail in humans exposed to frequent intestinal infections. We evaluated in mice the efficacy of subcutaneous vaccine injection as an alternative way to induce protective immunity, while reducing the dose and avoiding strain release in nature. A single subcutaneous dose of up to 10 8 CFU induced dose-dependent antibody production. At the dose of 10 7 CFU, i.e. 10 times less than via the oral route, it caused a modest skin reaction and protected 100% against bubonic and 80% against pneumonic plague, caused by high doses of Yersinia pestis. Bacteria migrating to lymph nodes and spleen, but not feces, were rapidly eliminated. Thus, subcutaneous injection of VTnF1 would represent a good alternative when dissemination in nature and human intestinal responsiveness are limitations.

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The immunological anatomy of the skin

Cited by 395 publications

References 99 publications

Highly Efficient, Massively-Parallel Single-Cell RNA-Seq Reveals Cellular States and Molecular Features of Human Skin Pathology

Highly Efficient, Massively-Parallel Single-Cell RNA-Seq Reveals Cellular States and Molecular Features of Human Skin Pathology

Trisk 95 as a Novel Skin Mirror for Normal and Diabetic Systemic Glucose Level

Subcutaneous vaccination with a live attenuated Yersinia pseudotuberculosis plague vaccine

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