Epidermal keratinocyte-specific STAT3 deficiency aggravated atopic dermatitis-like skin inflammation in mice through TSLP upregulation.

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases with complex pathogenesis involving epidermal barrier dysfunction, skin microbiome abnormalities and type-2-skewed immune dysregulation. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays critical roles in various biological processes. However, the role of STAT3 in epidermal keratinocytes in AD remains unclear. In this study, we generated an epidermal keratinocyte-specific Stat3-deficient mouse strain (termed Stat3 cKO mice). After topical 2,4-dinitrochlorobenzene (DNCB) treatment, Stat3 cKO mice developed worsened AD-like skin inflammation with increased Ki67+ cells, decreased filaggrin and loricrin expression, and downregulated S100A9 and LL37. The dominant microbial population in Stat3 cKO mice changed from Ralstonia to Staphylococcus. DNCB-treated Stat3 cKO mice displayed more infiltrating type-2 inflammatory cells, including mast cells, eosinophils, and CD4+T cells, accompanied by increased skin IL-4 and serum IgE levels. Moreover, thymic stromal lymphopoietin (TSLP), mainly produced by keratinocytes, was highly expressed in the ear skin of Stat3 cKO mice and chemoattracted more TSLPR+ cells. TSLP blockade significantly alleviated DNCB-induced AD-like skin inflammation in Stat3 cKO mice. Thus, epidermal keratinocyte-specific STAT3 deficiency can aggravate AD-like skin inflammation in mice, possibly through TSLP dysregulation.

The epidermal immune microenvironment plays a dominant role in psoriasis development, as revealed by mass cytometry.

Psoriasis is a common chronic inflammatory skin disease. The diversity and heterogeneity of immune cells in human skin have been studied in recent years, but the spatial distribution of immune cells at the single-cell level in the human psoriatic epidermis and dermis remains unclear. In this study, we mapped psoriatic skin immune cells from paired lesional, perilesional, and nonlesional skin samples using mass cytometry. Phenotypic dendritic cells (DCs) were found in the psoriatic epidermis and dermis. Psoriatic dermal CD1c+CD11b+ cDC2s migrated to the epidermis in the perilesional skin during the preinitiation stage. CD1c+CD11b+ cDC2s rapidly replaced EpCAM+CD11clow LC cells and initiated inflammation. Simultaneously, CD207+CD11chi LC and CD5+ T cells accumulated in the psoriatic epidermis and orchestrated epidermal inflammation in psoriasis. The immune cell pool in the psoriatic dermis primarily included APCs and T cells. However, unlike that in the dermis, the epidermal immune environment was more significant and coincided with the inflammation occurring during psoriasis.The epidermal immune microenvironment plays a dominant role in psoriasis. Langerhans cells, epidermis-resident memory T cells and macrophages together contribute to healthy epidermal immune homeostasis. However, psoriatic CD1c+CD11b+ epidermal cDC2s are positioned in the perilesional area, replacing EpCAM+CD11clow LCs rapidly and initiating inflammation. Epidermal CD141+ cDC1s, CD1c+ cDC2s, CD14+ moDCs, and BDCA2+ pDCs orchestrate psoriatic inflammation. Meanwhile, CD11chi LCs and CD5+ T cells accumulate in the psoriatic epidermis.

Mupirocin blocks imiquimod-induced psoriasis-like skin lesion by inhibiting epidermal isoleucyl-tRNA synthetase.

BACKGROUND: The Isoleucyl-tRNA synthetase (IARS) catalyzes isoleucine to the corresponding tRNA, maintaining the accuracy of gene translation. Its role in psoriasis has been not investigated so far. In this study, we aimed to investigate the mechanisms underlying the efficacy of IARS inhibitor, mupirocin, treatment for psoriasis. METHODS: The expression of IARS was determined by immunofluorescence, Western blot and qRT-PCR in normal healthy control- and psoriatic human skin. An imiquimod (IMQ) -induced psoriasis-like skin disease model was used to study the phenotypes changed by an IARS inhibitor, mupirocin (MUP). Endotypes were analyzed by RNA-seq, R&D Luminex multi-factor technique, ELISA, immunofluorescence and flow cytometry. Additionally, the effect of MUP on epidermal keratinocytes (KCs) were conducted in-vitro in primary cultured human KCs. RESULTS: We found the expression of IARS was higher in psoriatic skin than in healthy controls. In IMQ-induced psoriasis-like C57BL/6 J mouse model, MUP reversed IMQ-induced keratinocytes proliferation, expression of inflammatory cytokines and infiltration of immune cells. Furthermore, in cultured human keratinocytes, MUP inhibited proliferation, but promoted apoptosis, which may be related with STAT3 signaling pathway. CONCLUSION: Our finding of blocking the infiltration of immune cells by inhibiting the formation of IARS, could be one mechanism to explain the effect of MUP in the treatment of psoriasis. Developing strategies targeting suppression IARS should open new perspectives for the treatment of psoriasis. Video Abstract.

Actuators for Implantable Devices: A Broad View.

The choice of actuators dictates how an implantable biomedical device moves. Specifically, the concept of implantable robots consists of the three pillars: actuators, sensors, and powering. Robotic devices that require active motion are driven by a biocompatible actuator. Depending on the actuating mechanism, different types of actuators vary remarkably in strain/stress output, frequency, power consumption, and durability. Most reviews to date focus on specific type of actuating mechanism (electric, photonic, electrothermal, etc.) for biomedical applications. With a rapidly expanding library of novel actuators, however, the granular boundaries between subcategories turns the selection of actuators a laborious task, which can be particularly time-consuming to those unfamiliar with actuation. To offer a broad view, this study (1) showcases the recent advances in various types of actuating technologies that can be potentially implemented in vivo, (2) outlines technical advantages and the limitations of each type, and (3) provides use-specific suggestions on actuator choice for applications such as drug delivery, cardiovascular, and endoscopy implants.

Biologics for psoriasis patients under 18 years of age: Real-world evidence from the Chinese psoriasis real world evidence research group.

Background: Treatment for pediatric psoriasis is challenging because of the lack of real-world evidence, especially for biological therapies. Objectives: This study evaluated the efficacy and safety of biologics in children with psoriasis based on real-world evidence. Methods: Pediatric psoriasis patients aged <18 years who were treated with biologics in our hospital (2020-2022) were prospectively analyzed. Patients treated with adalimumab, secukinumab, or ixekizumab were followed up for at least 16 weeks, and 22 of 38 patients completed the 52-week observation period. Dermatologist raters were blinded to ensure the reliability of the PASI, BSA, and PGA score assessments. PASI 75 or PGA 0/1 at week 12 represented an efficient indicator. Results: Thirty-eight patients (20 males and 18 females; median age, 12.6 ± 4.1 years) were enrolled, and none were lost to follow-up. All participants were diagnosed with psoriasis, including plaque psoriasis (n = 36), nail psoriasis (n = 1), and pustular psoriasis (n = 1). Within 12 weeks, all patients achieved scores above PASI 75 and PGA 0/1. The average time to reach PASI 75 was 4.3 ± 2.0, 3.2 ± 1.8, and 2.4 ± 0.4 weeks in patients using adalimumab, secukinumab, and ixekizumab, respectively, and, 27.2% (3/11), 86.4% (19/22), and 75.0% (3/4) of these patients achieved PASI 100 at week 12, respectively. Moreover, 18 of 20 patients with plaque psoriasis maintained ≥PASI 75 after 52 weeks. The most commonly reported adverse effect was upper respiratory tract infection, and no severe adverse effects were reported. Conclusions: Our real-world data demonstrated the safety and effectiveness of adalimumab, secukinumab, and ixekizumab in children with psoriasis.

Sprouty1 exerts a preventive effect on the initiation of psoriasis by inhibiting innate immune antimicrobial peptide cathelicidin and immunocytes.

OBJECTIVES: Psoriasis is an immune-mediated skin disease dominated by the cutaneous immune system. Keratinocytes have been considered important triggers that initiate psoriasis. The key molecules and events of keratinocytes that link the innate immune system in psoriasis must be investigated in more detail. Human psoriasis skin and primary human keratinocyte were detected in vitro. Epidermis specific transgenic mouse strain (Krt14-Sprouty1 tg) was used to further investigate psoriasis-like skin inflammation in vivo. MATERIALS AND METHODS: Bulk RNA sequencing of primary human keratinocyte screened differentially expressed genes, which was confirmed by quantitative real time PCR and Western Blot (WB). Moreover, we concomitantly reviewed open-accessed published RNAseq datasets of human psoriatic skin from GEO database. Immunohistochemical staining and immunofluorescence were used to detect Sprouty1 (SPRY1) expression in human psoriatic skin with and without anti-psoriasis treatments. Krt14-Sprouty1 tg was used to further investigate psoriasis-like skin inflammation, and followed by Hematoxylin and Eosin (HE) Staining, enzyme linked immunosorbent assay (ELISA), Western Blot and flow cytometry. RESULTS: Our data showed that Sprouty1 was decreased in psoriatic skin and keratinocytes. In imiquimod-induced psoriasis-like skin inflammation, the production of cathelicidin (camp/LL37) was inhibited by suppressing signal transducer and activator of transcription3 (Stat3) activation when Sprouty1 overexpressed in mouse epidermal keratinocytes. Moreover, CD11b+CCR2+ dendritic cells, IL-17A+ γδT cells, and Ly6C+ CD11c+ monocyte-derived dendritic cells were decreased in Krt14-Sprouty1 tg (STG) imiquimod-induced cutaneous inflammation. CONCLUSIONS: These findings indicate that Sprouty1 expressed in keratinocytes has a suppressive role in imiquimod-induced skin inflammation mediated by inhibiting the production of cathelicidin. Collectively, Sprouty1 plays a preventive role in psoriatic skin. Our data provide new evidence for the pathogenesis of psoriatic keratinocytes, and the link cutaneous innate immunity, that indicated Sprouty1 is a potential novel therapeutic target.

Cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes.

Recent studies have illustrated that psoriatic lesions are innervated by dense sensory nerve fibers. Psoriatic plaques appeared to improve after central or peripheral nerve injury. Therefore, the nervous system may play a vital role in psoriasis. We aimed to clarify the expression of nerve fibers in psoriasis and their relationship with immune cells and keratinocytes, and to explore the effect of skin nerve impairment. Our results illustrated that nerve fibers in psoriatic lesions increased and were closely innervated around immune cells and keratinocytes. RNA-seq analysis showed that peripheral sensory nerve-related genes were disrupted in psoriasis. In spinal cord hemi-section mice, sensory impairment improved psoriasiform dermatitis and inhibited the abnormal proliferation of keratinocytes. Botulinum toxin A alleviated psoriasiform dermatitis by inhibiting the secretion of calcitonin gene-related peptide. Collectively, cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes. Neurological intervention may be a new treatment strategy for psoriasis.

OAS1, OAS2, and OAS3 Contribute to Epidermal Keratinocyte Proliferation by Regulating Cell Cycle and Augmenting IFN-1‒Induced Jak1‒Signal Transducer and Activator of Transcription 1 Phosphorylation in Psoriasis.

Psoriasis is a systemic immune‒mediated inflammatory disease characterized by hyperproliferation and abnormal differentiation of epidermal keratinocytes. Recent studies have identified IL-17 and IL-23 as key drivers of psoriasis pathogenesis, but the underlying molecular mechanisms remain unclear. The 2'-5'-oligoadenylate synthetases (OASs), namely, OAS1, OAS2, OAS3, and OASL, are a family of IFN-induced enzymes with multiple antiviral activities, but their role in psoriasis is unknown. In this study, we identified the overexpression of OAS1, OAS2, and OAS3 in human lesional psoriatic skin and serum and found that their expression was downregulated by biologics. Moreover, OASs were highly expressed in epidermal keratinocytes, epidermal dendritic cells, epidermal CD3+ T cells, dermal antigen-presenting cells, and dermal T cells from the psoriatic epidermis and dermis, as determined by flow cytometry. In addition, OASs were upregulated by poly(I:C), poly(dA:dT), and IFN-1s but downregulated by Jak inhibitors in normal human epidermal keratinocytes. Furthermore, silencing of OASs inhibited the phosphorylation of Jak1 and signal transducer and activator of transcription 1. Knockdown of OASs suppressed keratinocyte proliferation by inhibiting cell cycle progression. Thus, OASs may be therapeutic biomarkers in psoriasis.

Cutaneous and Systemic Psoriasis: Classifications and Classification for the Distinction.

Psoriasis is a chronic multisystem inflammatory disease that affects ~0.1-1.5% of the world population. The classic cutaneous manifestation of psoriasis is scaly erythematous plaques, limited or widely distributed. Moreover, psoriasis could be associated with comorbidities like psoriatic arthritis, metabolic syndrome, diabetes, cardiovascular disease, nephropathy, bowel disease, and brain diseases. In this review, we suggest that psoriasis should be classified as cutaneous psoriasis or systemic psoriasis and propose the classification for distinction. This would help to better understand and manage psoriasis.

Quantitative Proteomic Profile of Psoriatic Epidermis Identifies OAS2 as a Novel Biomarker for Disease Activity.

Psoriasis is a common chronic inflammatory systemic disease. Epidermal proteins are considered to be important in maintaining skin barrier function, innate immunity, and inflammation. To define more possible roles of the epidermis in the pathogenesis of psoriasis, quantified proteomic analysis was used to screen and analyze the differentially expressed epidermal proteins between 16 psoriasis patients and 15 healthy controls. Upregulated differential expression proteins (DEPs) include several significant functional protein clusters, including antimicrobial peptides (AMPs) and antiviral proteins (AVPs). The levels of 2-5-oligoadenylate synthase 2 (OAS2) in both epidermis and serum levels were significantly elevated in psoriasis and were also positively correlated with Psoriasis Area Severity Index (PASI) scores and Body Surface Area (BSA) scores. Moreover, OAS2 expression in psoriatic skin significantly decreased after IL-17R mono-antibody treatment. It has been clarified that inflamed keratinocytes were the main source of abnormally increased OAS2 in psoriasis skin by immunofluorescence and primary cell cultures. Keratinocyte-derived OAS2 can be induced by not only IFNß, but also psoriasis associated cytokines like IL-17A and IL-6. This study revealed that AMPs and AVPs are two important functional protein clusters altering innate immune in psoriatic epidermis. OAS2 is a novel potential sensitive biomarker, which could predict the severity and activity of psoriasis, and could also be used as an indicator to evaluate or monitor the efficacy of clinical treatment.

TNFα inhibitor may be effective for severe COVID-19: learning from toxic epidermal necrolysis.

Increased inflammatory cytokines [such as tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6)] are observed in COVID-19 patients, especially in the severe group. The phenomenon of a cytokine storm may be the central inducer of apoptosis of alveolar epithelial cells, which leads to rapid progression in severe group patients. Given the similarities of clinical features and pathogenesis between toxic epidermal necrolysis (TEN) and COVID-19, we hypothesize that the application of etanercept, an inhibitor of TNFα, could attenuate disease progression in severe group COVID-19 patients by suppressing systemic auto-inflammatory responses. The reviews of this paper are available via the supplemental material section.

Suppressor of Fused Inhibits Skin Wound Healing.

Objectives: To investigate the effect of suppressor of fused (Sufu) on epidermal and dermal cellular properties and in wound healing. Approach: Transgenic (TG) mice overexpressing human Sufu (hSufu) in the epidermis were applied to investigate the effects of Sufu on epidermal and dermal cellular properties and in wound healing. Results: Histological staining revealed a reduction of epidermal and dermal thickness and an increase of hypodermal adipose tissue in homozygous K14-hSufu TG mice when compared with wild-type (WT) controls. TG mice exhibited significantly delayed skin wound healing. Moreover, the migratory and proliferative capabilities of cultured keratinocytes were decreased in K14-hSufuTG mice. Transforming growth factor-ß treatment increased the expression of α-smooth muscle actin more in WT than in TG fibroblasts. Sufu overexpression significantly decreased the expression of ß-catenin, glioma transcription factor 1 (Gli1), and matrix metalloproteinase-3 in wounds of K14-hSufu TG mice when compared with controls, probably indicating a delaying effect of Sufu on wound healing via blocking the hedgehog (Hh)/Gli and Wnt/ß-catenin pathway. Innovation: Our results indicate a new property of Sufu in the process of skin wound healing. It provides an important basis for Sufu as a potential target for skin wound healing. Conclusion: Our findings suggest that Sufu overexpression in the epidermis impairs wound healing via dampening the Hh/Gli and Wnt/ß-catenin signaling pathway. These data provide an important basis for further analyses of Sufu in skin wound healing.

Fast Electrochemical Netting of Composite Chains for Transferable Highly Conductive Polymeric Nanofilms.

Broad applications of electropolymerized conducting polymers (CPs) often prefer thinner soft electrodes to comply with downscaling of the fabrication resolution. However, high conductivity of existing CP films vanishes as thickness decreases to the nanoscale (i.e., below 100 nm), with an unclear mechanism so far. In this study, with an unprecedented family of polypyrrole (PPy) nanofilms that can be easily transferred in a fast and contamination-free manner, we are able to trace the initial development of electrical conductance along with chains' arrangement starting from the very early electrochemical deposition. Our results evidence that the classical nodular polymeric aggregation fundamentally accounts for the persistent losses of interchain connectivity and macroscopic conductivity at a limited thickness. Surprisingly, this seemingly disadvantageous structure can be altered into a large conjugated network to robustly restore the conductivity back to over 80 S cm-1 even below 100 nm, while the controllable formation, growth, and collapse of such networks radically vary the conductivity over a range of 3 orders of magnitude (0.8-129 S cm-1). These observations depict the first physical picture detailing how the long-range conductivity builds up in a growing conjugated network, which opens a route to fast synthesis and diverse applications of such highly conductive CP nanofilms.

Exosomal microRNA profiles from serum and cerebrospinal fluid in neurosyphilis.

OBJECTIVE: Changes in microRNAs (miRNAs) in the cerebrospinal fluid (CSF) are associated with different neurological diseases. Since alternations of miRNAs in neurosyphilis are insufficiently investigated, we analysed miRNAs in the CSF of patients suffering from neurosyphilis. METHODS: Exosomes were isolated from serum and CSF. Levels of 44 miRNAs were determined using quantitative real-time PCR-based miRNA array. RESULTS: In patients with neurosyphilis (NSP), miR-590-5p, miR-570-3p and miR-570-5p were upregulated in the CSF and serum, when compared with patients with syphilis without neurosyphilis (SP). miR-590-5p and miR-570-3p were significantly upregulated (p<0.001). The expression of miR-21-5p was upregulated only in the CSF of NSP. Significant downregulation was observed for miR-93-3p in the CSF and serum of NSP. No statistical difference was found in the expression of miR-7-5p, miR-1307-5p, miR-203a-3p, miR-16, miR-23b-3p and miR-27b-5p in the CSF and serum of NSP and SP. CONCLUSION: For the first time, regulation profiles in miRNA in the CSF and serum were analysed in NSP. We found significant differences in upregulation and downregulation. Therefore, miRNAs may be potential biomarkers for the presence of neurosyphilis.

Comparative expression of PEDF and VEGF in human epidermal keratinocytes and dermal fibroblasts: from normal skin to psoriasis.

Vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) have been shown to keep angiogenesis activation and inhibition in balance in normal and pathological conditions. In this study, we examined the expression of VEGF and PEDF in keratinocytes and fibroblasts from normal and psoriatic skin to evaluate their potential roles and interactions in the development of psoriasis. The expression of VEGF and PEDF was detected in normal and psoriatic skin ex vivo and in co-cultured keratinocytes and fibroblasts in vitro, and increased in keratinocytes and fibroblasts from psoriatic skin compared with those cells from normal skin. Our results suggest that PEDF act as a multipotent factor in the skin and the imbalance of PEDF and VEGF may be responsible for the transformation from normal skin to psoriasis.

Rottlerin as a therapeutic approach in psoriasis: Evidence from in vitro and in vivo studies.

Rottlerin is a natural polyphenolic compound that was initially indicated as a PKCδ inhibitor. However, it was recently revealed that it may target a number of molecules and have biological effects on various cell types and is considered as a possible agent for tumor and cell proliferative diseases. Psoriasis is a chronic inflammatory cutaneous disorder with undefined etiology and is characterized by abnormal cellular proliferation, angiogenesis, and inflammation. Therefore, this paper investigates the regulatory effects of rottlerin on normal human epidermal keratinocytes (NHEKs) and imiquimod (IMQ)-induced psoriasiform (IPI) lesions. In vitro results showed that rottlerin inhibited cell proliferation in NHEKs through growth arrest and NFκB inhibition. It may also induce apoptosis in an autophagy-dependent pathway. We found that rottlerin inhibited human microvascular endothelial cells tube formation on matrigel. Rottlerin also decreased the cell senescence of keratinocytes and intracellular ROS generation, which indicated its antioxidant effect. We also showed that rottlerin affects the expression of keratinocyte proliferation biomarkers. In 12-O-tetradecanoylphorbol13-acetate (TPA)-induced keratinocytes, rottlerin significantly inhibited the expression of the induced pro-inflammatory cytokines in keratinocytes. An animal experiment provided the corresponding evidence based on this evidence in vitro, by using IPI model, we found that rottlerin could relieve the psoriasiform of BALB/c mice by inhibiting keratinocyte proliferation, inflammatory cell infiltration, and vascular proliferation. In conclusion, our results suggest that rottlerin may prove useful in the development of therapeutic agents against psoriasis. However, the deep mechanism still requires further study.

Flexible Photocatalytic Composite Film of ZnO-Microrods/Polypyrrole.

Zinc oxide (ZnO)-based photoanodes with sunlight photocatalytic activity are widely used in dye-sensitized solar cells. Presently, most of such electrodes are inflexible due to the rigidness of ZnO and substrate, thus hindering their application in flexible electronics. Here, we report a flexible composite film of ZnO microrod arrays and polypyrrole (PPy) featuring significant flexibility, durability, and photocatalytic capability under visible light. In this composite film, the upper section of the ZnO microrods is coated with an approximately 400 nm thick PPy shell, and the lower section of the ZnO microrods is tightly embedded into an underlying PPy base layer, creating an integrated heterogeneous structure. The upper PPy coating shell serves as a photosensitizer for the ZnO-based photocatalysis, while the lower PPy base layer facilitates electron transport to the substrate and mechanically reinforces the ZnO microrod arrays. Under visible light, this facile structure achieves much higher photocatalytic efficiency in comparison to pure ZnO microrod arrays or PPy film, degrading methylene blue at a rate of 0.22%/min. This photocatalytic composite film may find promising applications in flexible solar cells to power stretchable and wearable electronics.