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

2019 ◽  
Author(s):  
Travis K Hughes ◽  
Marc H Wadsworth ◽  
Todd M Gierahn ◽  
Tran Do ◽  
David Weiss ◽  
...  
Keyword(s):  
Single Cell ◽  
Human Skin ◽  
Skin Diseases ◽  
Parenchymal Cell ◽  
Skin Inflammation ◽  
Microtiter Plate ◽  
Massively Parallel ◽  
Inflammatory Skin Diseases ◽  
Molecular Features ◽  
Methodological Advance

SUMMARYThe development of high-throughput single-cell RNA-sequencing (scRNA-Seq) methodologies has empowered the characterization of complex biological samples by dramatically increasing the number of constituent cells that can be examined concurrently. Nevertheless, these approaches typically recover substantially less information per-cell as compared to lower-throughput microtiter plate-based strategies. To uncover critical phenotypic differences among cells and effectively link scRNA-Seq observations to legacy datasets, reliable detection of phenotype-defining transcripts – such as transcription factors, affinity receptors, and signaling molecules – by these methods is essential. Here, we describe a substantially improved massively-parallel scRNA-Seq protocol we term Seq-Well S^3 (“Second-Strand Synthesis”) that increases the efficiency of transcript capture and gene detection by up to 10- and 5-fold, respectively, relative to previous iterations, surpassing best-in-class commercial analogs. We first characterized the performance of Seq-Well S^3 in cell lines and PBMCs, and then examined five different inflammatory skin diseases, illustrative of distinct types of inflammation, to explore the breadth of potential immune and parenchymal cell states. Our work presents an essential methodological advance as well as a valuable resource for studying the cellular and molecular features that inform human skin inflammation.

Single-cell analysis of human skin identifies CD14+ type 3 dendritic cells co-producing IL1B and IL23A in psoriasis

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
Satoshi Nakamizo ◽  
Charles-Antoine Dutertre ◽  
Ahad Khalilnezhad ◽  
Xiao Meng Zhang ◽  
Shawn Lim ◽  
...  
Keyword(s):  
Single Cell ◽  
Skin Diseases ◽  
Single Cell Analysis ◽  
Myeloid Cell ◽  
Molecular Characteristics ◽  
Inflammatory Skin Diseases ◽  
Cell Responses ◽  
Cell Flow Cytometry ◽  
Type 3 ◽  
Macrophage Subsets

Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell (DC)–mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA sequencing of lesional and nonlesional AD and PSO skin to identify macrophages and all DC subsets, including the newly described mature LAMP3+BIRC3+ DCs enriched in immunoregulatory molecules (mregDC) and CD14+ DC3. By integrating our indexed data with published skin datasets, we generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin. Importantly, we found that CD14+ DC3s increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathological in PSO. Our study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution, and identifies CD14+ DC3s as potential promoters of inflammation in PSO.

scholarly journals 1448 Development of immune-competent human skin constructs to model inflammatory skin diseases

2018 ◽  
Vol 138 (5) ◽  
pp. S246
Author(s):  
J. Shin ◽  
H. Abaci ◽  
Z. Guo ◽  
F. Magrelli ◽  
A. Pappalardo ◽  
...  
Keyword(s):  
Human Skin ◽  
Skin Diseases ◽  
Inflammatory Skin Diseases ◽  
Inflammatory Skin

scholarly journals IL-1 Family Antagonists in Mouse and Human Skin Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Praxedis Martin ◽  
Jérémie D. Goldstein ◽  
Loïc Mermoud ◽  
Alejandro Diaz-Barreiro ◽  
Gaby Palmer
Keyword(s):  
Skin Diseases ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Skin Inflammation ◽  
Cell Type ◽  
Inflammatory Skin Diseases ◽  
Innate And Adaptive Immunity ◽  
Skin Biology

Interleukin (IL)-1 family cytokines initiate inflammatory responses, and shape innate and adaptive immunity. They play important roles in host defense, but excessive immune activation can also lead to the development of chronic inflammatory diseases. Dysregulated IL-1 family signaling is observed in a variety of skin disorders. In particular, IL-1 family cytokines have been linked to the pathogenesis of psoriasis and atopic dermatitis. The biological activity of pro-inflammatory IL-1 family agonists is controlled by the natural receptor antagonists IL-1Ra and IL-36Ra, as well as by the regulatory cytokines IL-37 and IL-38. These four anti-inflammatory IL-1 family members are constitutively and highly expressed at steady state in the epidermis, where keratinocytes are a major producing cell type. In this review, we provide an overview of the current knowledge concerning their regulatory roles in skin biology and inflammation and their therapeutic potential in human inflammatory skin diseases. We further highlight some common misunderstandings and less well-known observations, which persist in the field despite recent extensive interest for these cytokines.

scholarly journals JNK1 Signaling Downstream of the EGFR Pathway Contributes to Aldara®-Induced Skin Inflammation

2021 ◽  
Vol 11 ◽  
Author(s):  
Aurore Le ◽  
Abdulkader Azouz ◽  
Séverine Thomas ◽  
Nicolas Istaces ◽  
Muriel Nguyen ◽  
...  
Keyword(s):  
Inflammatory Markers ◽  
Skin Diseases ◽  
Myeloid Cells ◽  
Skin Inflammation ◽  
Inflammasome Activation ◽  
Inflammatory Skin Diseases ◽  
Egfr Signaling Pathway ◽  
Egfr Ligands

c-Jun N-terminal protein kinase 1 (JNK1) is involved in multiple biological processes but its implication in inflammatory skin diseases is still poorly defined. Herein, we studied the role of JNK1 in the context of Aldara®-induced skin inflammation. We observed that constitutive ablation of JNK1 reduced Aldara®-induced acanthosis and expression of inflammatory markers. Conditional deletion of JNK1 in myeloid cells led to reduced skin inflammation, a finding that was associated with impaired Aldara®-induced inflammasome activation in vitro. Next, we evaluated the specific role of JNK1 in epidermal cells. We observed reduced Aldara®-induced acanthosis despite similar levels of inflammatory markers. Transcriptomic and epigenomic analysis of keratinocytes revealed the potential involvement of JNK1 in the EGFR signaling pathway. Finally, we show that inhibition of the EGFR pathway reduced Aldara®-induced acanthosis. Taken together, these data indicate that JNK1 plays a dual role in the context of psoriasis by regulating the production of inflammatory cytokines by myeloid cells and the sensitivity of keratinocytes to EGFR ligands. These results suggest that JNK1 could represent a valuable therapeutic target in the context of psoriasis.

scholarly journals Lack of Endogenous Annexin A1 Increases Mast Cell Activation and Exacerbates Experimental Atopic Dermatitis

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 51 ◽  
Author(s):  
Jéssica Parisi ◽  
Mab Corrêa ◽  
Cristiane Gil
Keyword(s):  
Atopic Dermatitis ◽  
Mast Cell ◽  
Cell Activation ◽  
Skin Diseases ◽  
Skin Inflammation ◽  
Skin Lesions ◽  
Mast Cell Activation ◽  
Skin Thickness ◽  
Annexin A1 ◽  
Inflammatory Skin Diseases

Annexin A1 (AnxA1) is a protein with potent anti-inflammatory actions and an interesting target that has been poorly explored in skin inflammation. This work evaluated the lack of endogenous AnxA1 in the progression of ovalbumin (OVA)-induced atopic dermatitis (AD)-like skin lesions. OVA/Alum-immunized C57BL/6 male wild-type (WT) and AnxA1 null (AnxA1-/-) mice were challenged with drops containing OVA on days 11, 14–18 and 21–24. The AnxA1-/- AD group exhibited skin with intense erythema, erosion and dryness associated with increased skin thickness compared to the AD WT group. The lack of endogenous AnxA1 also increased IgE relative to WT animals, demonstrating exacerbation of the allergic response. Histological analysis revealed intense eosinophilia and mast-cell activation in AD animals, especially in AnxA1-/-. Both AD groups increased skin interleukin (IL)-13 levels, while IL-17A was upregulated in AnxA1-/- lymph nodes and mast cells. High levels of phosphorylated ERK were detected in keratinocytes from AD groups. However, phospho-ERK levels were higher in the AnxA1-/- when compared to the respective control groups. Our results suggest AnxA1 as an important therapeutic target for inflammatory skin diseases.

scholarly journals Synergistic effect of tolfenamic acid and glycyrrhizic acid on TPA-induced skin inflammation in mice

MedChemComm ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 1819-1827 ◽  
Author(s):  
Wenfeng Liu ◽  
Shun Huang ◽  
Yonglian Li ◽  
Xi Zheng ◽  
Kun Zhang
Keyword(s):  
Synergistic Effect ◽  
Glycyrrhizic Acid ◽  
Skin Diseases ◽  
Skin Inflammation ◽  
Tolfenamic Acid ◽  
Inflammatory Skin Diseases ◽  
Inflammatory Skin

Combinational use of tolfenamic acid and glycyrrhizic acid has importantly enhanced influences on treating inflammatory skin diseases.

scholarly journals Anti-Inflammatory Activity of a Medicinal Herb Extract Mixture, HM-V, on an Animal Model of DNCB-Induced Chronic Skin Inflammation

Plants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1546
Author(s):  
Sungbae Park ◽  
Sangmin Lee ◽  
Youngho Weon ◽  
Taewook Kim ◽  
Hakwon Kim ◽  
...  
Keyword(s):  
Animal Model ◽  
Inflammatory Cytokines ◽  
Skin Diseases ◽  
Skin Inflammation ◽  
Medicinal Herb ◽  
Inflammatory Skin Diseases ◽  
Tnf Α ◽  
Ifn Γ ◽  
Chronic Skin ◽  
Pro Inflammatory Cytokines

Chronic inflammatory skin diseases, such as atopic dermatitis, are caused by the accumulation of immune cells and the overproduction of chemokines, including CCL17 and CCL22, due to the activation of pro-inflammatory cytokines secreted from keratinocytes. In the present study, the inhibitory activity of HM-V on tumor necrosis factor alpha (TNF-α)/interferon gamma (IFN-γ)-induced pro-inflammatory cytokines was examined in human keratinocytes (HaCaTs) and 2,4-dinitrofluorobenzene (DNCB)-induced chronic skin contact dermatitis animal models. Traditional Asian medicinal herb extracts mixture (HM-V), which have been extensively used in Asian medicine, were utilized. In TNF-α/IFN-γ-induced HaCaTs, HM-V strongly inhibited mRNA and protein expression of CCL17 and CCL22 in a concentration-dependent manner. The expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 was also inhibited. Therefore, localized administration of HM-V in the DNCB-induced animal model alleviated immune cell deposition and skin inflammation. The results indicate that HM-V exerts inhibitory effects on keratinocyte production of CCL17 and CCL22. Furthermore, HM-V may be a useful anti-inflammatory agent for the prevention and treatment of inflammatory skin diseases.

scholarly journals Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Psoriasis-like Skin Inflammation

2020 ◽  
Author(s):  
Yuli Zhang ◽  
Jianjun Yan ◽  
Zhengjun Li ◽  
Qing Sun
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Western Blotting ◽  
Skin Diseases ◽  
Skin Inflammation ◽  
Human Umbilical Cord ◽  
Hacat Cells ◽  
Inflammatory Skin Diseases

Abstract Background Exosomes are nanovesicles secreted from endosomal membranes. The immunomodulatory effect of mesenchymal stem cells (MSCs) is mediated by MSCs-derived exosomes (MSCs-exo). MSCs-exo are attractive candidates for use in cell therapy for several inflammatory diseases including psoriasis. We investigated whether exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-Exo) ameliorate psoriasis-like skin inflammation via the IL-23/IL-17 axis. Methods HucMSCs-Exo were isolated by differential ultracentrifugation. Imiquimod (IMQ)-induced mice were subcutaneously injected with hucMSCs-Exo on days 0, 2 and 4. H&E staining and Western blotting were performed, and tissue histopathology and STAT3/p-STAT3, IL-17, IL-23, and CCL20 levels were assessed. HucMSCs-Exo were co-cultured with dendritic cells (DCs) and HaCat cells in vitro. Western blotting, flow cytometry and ELISAs were then performed to measure STAT3/p-STAT3, IL-17, IL-23, and CCL20 levels. Results Subcutaneous injection of hucMSCs-Exo significantly ameliorated symptoms and diminished the clinical and pathological scores of psoriasis in IMQ-induced mice. In MSCs-exo-treated mice, STAT3/p-STAT3, IL-17, IL-23 and CCL20 levels were decreased. HucMSCs-Exo co-cultured in vitro with DCs suppressed DC maturation and activation and inhibited IL-23 secretion. HucMSCs-Exo co-cultured with HaCat cells reduced STAT3/p-STAT3, IL-17, IL-23, and CCL20 levels. Conclusions HucMSCs-Exo can effectively ameliorate psoriasis-like skin inflammation in mice via the IL-23/IL-17 axis. Furthermore, hucMSCs-Exo exhibit immunomodulatory potency by inhibiting the maturation and activation of DCs and blocking the positive feedback effect of IL-17 on keratinocytes. Our data offer a novel therapeutic approach for chronic inflammatory skin diseases such as psoriasis by leveraging the immunomodulatory effects of hucMSCs-Exo.

scholarly journals The Role of Gut Microbiome in Psoriasis: Oral Administration of Staphylococcus aureus and Streptococcus danieliae Exacerbates Skin Inflammation of Imiquimod-Induced Psoriasis-Like Dermatitis

2020 ◽  
Vol 21 (9) ◽  
pp. 3303 ◽  
Author(s):  
Karin Okada ◽  
Yoshiaki Matsushima ◽  
Kento Mizutani ◽  
Keiichi Yamanaka
Keyword(s):  
Gut Microbiome ◽  
Skin Diseases ◽  
Skin Inflammation ◽  
Gut Bacteria ◽  
Rrna Gene ◽  
Skin Microbiome ◽  
Inflammatory Skin Diseases ◽  
Fecal Microbiome ◽  
Tnf Α ◽  
Inflammatory Skin

Psoriasis is one of the common chronic inflammatory skin diseases in which inflammatory cytokines such as IL-17 and TNF-α play critical roles. Skin microbiome of psoriasis patients is reported to have elevated Staphylococcus and Streptococcus genus. There are controversial reports about gut microbiome of psoriasis patients, and whether the diversity of bacteria in genus level is decreased or not is still unclear. Moreover, it is not yet known if these gut bacteria would be the cause of the inflammation or the result of the inflammation. We analyzed the gut microbiome of the inflammatory skin model mouse (keratinocyte-specific caspase-1 transgenic (Kcasp1Tg) mouse), by analyzing the 16S rRNA gene. Staphylocuccus aureus and Streptococcus danieliae were abundant in Kcasp1Tg mouse fecal microbiome. These dominant bacteria as well as recessive control bacteria were orally administrated to antibiotic-treated wild type mice, and set up imiquimod-induced psoriasis-like skin inflammation model. The skin inflammation including ear thickness and histopathological findings was analyzed. The exacerbated skin lesions with the elevated levels of TNF-α, IL-17A, IL-17F, and IL-22 were observed in Staphylocuccus aureus and Streptococcus danieliae administrated groups. Our finding suggests that there is affinity between skin inflammation severity and certain gut bacteria leading to a vicious cycle: skin inflammation populates certain gut bacteria which itself worsens the skin inflammation. This is the first report on Staphylocuccus aureus and Streptococcuus danieliae effects in vivo. Not only treating the skin lesion but also treating the gut microbiome could be the future key treatment for inflammatory skin disease such as psoriasis.

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