IL-17D-induced inhibition of DDX5 expression in keratinocytes amplifies IL-36R-mediated skin inflammation.

Aberrant RNA splicing in keratinocytes drives inflammatory skin disorders. In the present study, we found that the RNA helicase DDX5 was downregulated in keratinocytes from the inflammatory skin lesions in patients with atopic dermatitis and psoriasis, and that mice with keratinocyte-specific deletion of Ddx5 (Ddx5∆KC) were more susceptible to cutaneous inflammation. Inhibition of DDX5 expression in keratinocytes was induced by the cytokine interleukin (IL)-17D through activation of the CD93-p38 MAPK-AKT-SMAD2/3 signaling pathway and led to pre-messenger RNA splicing events that favored the production of membrane-bound, intact IL-36 receptor (IL-36R) at the expense of soluble IL-36R (sIL-36R) and to the selective amplification of IL-36R-mediated inflammatory responses and cutaneous inflammation. Restoration of sIL-36R in Ddx5∆KC mice with experimental atopic dermatitis or psoriasis suppressed skin inflammation and alleviated the disease phenotypes. These findings indicate that IL-17D modulation of DDX5 expression controls inflammation in keratinocytes during inflammatory skin diseases.

When SLC46A2 delivers cargo into keratinocytes.

How pattern recognition receptors NOD1 and NOD2 sense bacterial muropeptides from extracellular bacteria to drive keratinocyte inflammation remains unclear. In this issue of Immunity, Bharadwaj et al. show that the solute carrier 46A2 (SLC46A2) delivers DAP-muropeptides into the cytosol to drive NOD1 activation in keratinocytes and elicit skin inflammation during psoriasis.

An Interleukin-25-Mediated Autoregulatory Circuit in Keratinocytes Plays a Pivotal Role in Psoriatic Skin Inflammation.

Psoriasis is a chronic autoinflammatory skin disease. Although interleukin-17, derived from lymphocytes, has been shown to be critical in psoriasis, the initiation and maintenance of chronic skin inflammation has not been well understood. IL-25 (also called IL-17E), another IL-17 family cytokine, is well known to regulate allergic responses and type 2 immunity. Here we have shown that IL-25, also highly expressed in the lesional skin of psoriasis patients, was regulated by IL-17 in murine skin of a imiquimod (IMQ)-induced psoriasis model. IL-25 injection induced skin inflammation, whereas germline or keratinocyte-specific deletion of IL-25 caused resistance to IMQ-induced psoriasis. Via IL-17RB expression in keratinocytes, IL-25 stimulated the proliferation of keratinocytes and induced the production of inflammatory cytokines and chemokines, via activation of the STAT3 transcription factor. Thus, our data demonstrate that an IL-17-induced autoregulatory circuit in keratinocytes is mediated by IL-25 and suggest that this circuit could be targeted in the treatment of psoriasis patients.

Keratinocytes in the pathogenesis, phenotypic switch, and relapse of psoriasis.

Although biologics have achieved tremendous success in the treatment of psoriasis and revolutionized the clinical management of the disease, certain issues arise during treatments, including the phenotypic switch from psoriasis to other skin disorders and the recurrence of psoriasis after the cessation of biologic treatment. Here we provide a concise overview of the roles of keratinocytes in the pathogenesis of psoriasis, elucidate the involvement of keratinocytes in the phenotypic switch and relapse of psoriasis, and address the challenges encountered in both basic and clinical research on psoriasis.

Scarring Skin: Mechanisms and Therapies.

Skin injury always results in fibrotic, non-functional scars in adults. Although multiple factors are well-known contributors to scar formation, the precise underlying mechanisms remain elusive. This review aims to elucidate the intricacies of the wound healing process, summarize the known factors driving skin cells in wounds toward a scarring fate, and particularly to discuss the impact of fibroblast heterogeneity on scar formation. To the end, we explore potential therapeutic interventions used in the treatment of scarring wounds.

SALSA-Net: Explainable Deep Unrolling Networks for Compressed Sensing.

Deep unrolling networks (DUNs) have emerged as a promising approach for solving compressed sensing (CS) problems due to their superior explainability, speed, and performance compared to classical deep network models. However, the CS performance in terms of efficiency and accuracy remains a principal challenge for approaching further improvements. In this paper, we propose a novel deep unrolling model, SALSA-Net, to solve the image CS problem. The network architecture of SALSA-Net is inspired by unrolling and truncating the split augmented Lagrangian shrinkage algorithm (SALSA) which is used to solve sparsity-induced CS reconstruction problems. SALSA-Net inherits the interpretability of the SALSA algorithm while incorporating the learning ability and fast reconstruction speed of deep neural networks. By converting the SALSA algorithm into a deep network structure, SALSA-Net consists of a gradient update module, a threshold denoising module, and an auxiliary update module. All parameters, including the shrinkage thresholds and gradient steps, are optimized through end-to-end learning and are subject to forward constraints to ensure faster convergence. Furthermore, we introduce learned sampling to replace traditional sampling methods so that the sampling matrix can better preserve the feature information of the original signal and improve sampling efficiency. Experimental results demonstrate that SALSA-Net achieves significant reconstruction performance compared to state-of-the-art methods while inheriting the advantages of explainable recovery and high speed from the DUNs paradigm.

The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury.

Epithelial keratinocyte proliferation is an essential element of wound repair, and abnormal epithelial proliferation is an intrinsic element in the skin disorder psoriasis. The factors that trigger epithelial proliferation in these inflammatory processes are incompletely understood. Here we have shown that regenerating islet-derived protein 3-alpha (REG3A) is highly expressed in keratinocytes during psoriasis and wound repair and in imiquimod-induced psoriatic skin lesions. The expression of REG3A by keratinocytes is induced by interleukin-17 (IL-17) via activation of keratinocyte-encoded IL-17 receptor A (IL-17RA) and feeds back on keratinocytes to inhibit terminal differentiation and increase cell proliferation by binding to exostosin-like 3 (EXTL3) followed by activation of phosphatidylinositol 3 kinase (PI3K) and the kinase AKT. These findings reveal that REG3A, a secreted intestinal antimicrobial protein, can promote skin keratinocyte proliferation and can be induced by IL-17. This observation suggests that REG3A may mediate the epidermal hyperproliferation observed in normal wound repair and in psoriasis.

Lipopeptide 78 from Staphylococcus epidermidis Activates ß-Catenin To Inhibit Skin Inflammation.

The appropriate inflammatory response is essential for normal wound repair, and skin commensal Staphylococcus epidermidis has been shown to regulate TLR3-mediated inflammatory response to maintain skin homeostasis after injury. However, the underlying mechanism by which S. epidermidis regulates wound-induced inflammation remains largely unexplored. In this study we identified a previously unknown lipopeptide 78 (LP78) from S. epidermidis and showed that LP78 inhibited TLR3-mediated skin inflammation to promote wound healing. Skin injury activated TLR3/NF-κB to promote the interaction of p65 and PPARγ in nuclei and then initiated the inflammatory response in keratinocytes. LP78 activated TLR2-SRC to induce ß-catenin phosphorylation at Tyr654 The phospho-ß-catenin translocated into nuclei to bind to PPARγ, thus disrupting the interaction between p65 and PPARγ. The disassociation between p65 and PPARγ reduced the expression of TLR3-induced inflammatory cytokines in skin wounds of normal and diabetic mice, which correlated with accelerated wound healing. Our data demonstrate that S. epidermidis-derived LP78 inhibits skin inflammation to promote wound healing and suggest that LP78 might be a potential compound for the treatment of delayed or unhealed wounds.

Lipopolysaccharides Inhibit REG3A Self-Aggregation on Gold Nanoparticles: A Combined Study of Multivariate Analysis on Time-Resolved Localized Surface Plasmon Resonance Spectra and Molecular Modeling.

Aggregation behavior of proteins on the surface of gold nanoparticles (AuNPs) has been extensively studied for its promising applications in biosensing, bioimaging, photodynamic therapy, drug delivery, etc. In this work, we studied adsorption kinetics of an antimicrobial protein, regenerating islet-derived protein 3-alpha (REG3A), on the surface of as-synthesized citrate-capped AuNPs under the influence of lipopolysaccharides (LPSs), with a combined method of UV-vis spectroscopy, multivariate analysis, and molecular dockings. In the AuNPs-REG3A binary system, a component with an "up-and-down" signal was detected by the in-depth data analysis on time-resolved spectroscopic data, corresponding to the protein agglomeration and exfoliation observed in transmission electron microscopy and atomic force microscopy experiments. Intriguingly, LPSs can rescue the spectral oddity-the adsorption pattern in the AuNPs-REG3A-LPS ternary system becomes normal and similar to a typical single-layer mode as in our previous study of the serum albumin-AuNP system ( Ren , X. ; et al., Spectrosc. Lett. , 2016 , 49 , 434 - 443 ). The following molecular modeling suggests that LPS molecules mainly interact with three segments of REG3A amino acid sequences, i.e., P109-T110-Q111-G112, P115-N116, and P137-S138-T139. The latter two protein-ligand interactions impair the REG3A-REG3A protein-protein interaction between the two subunits (E114-P115-N116-G117-E118 and N136-P137-S138-T139-I140). Thus, our results elucidate the LPS inhibitory effect on fibrous protein self-aggregation at the AuNP surface, and molecular dockings give a plausible mechanism to rationalize the competition among protein-protein and protein-ligand interactions.

Therapeutic antibodies that target inflammatory cytokines in autoimmune diseases.

Inflammatory cytokines are key regulators of immune responses. Persistent and excessive production of inflammatory cytokines underscores the development of autoimmune diseases. Therefore, neutralizing inflammatory cytokines or antagonizing their receptor function is considered as a useful therapeutic strategy to treat autoimmune diseases. To achieve the success of such a strategy, understanding of the complex actions of these cytokines and cytokine networks is required. In this review we focus on four inflammatory cytokines--tumor necrosis factor α (TNFα), interleukin-6 (IL-6), IL-23 and IL-17--and dissect how the dysregulation of these cytokines regulates autoimmune diseases. On the basis of pre-clinical and clinical data, we specifically discuss the therapeutic rationale for targeting these cytokines and describe the potential adverse effects.

[Using the Cognitive Behavioral Therapy to Improve the Mental Health of Women With Breast Cancer].

Previous studies have shown that patients with breast cancer may suffer from symptoms of psychological distress, such as: depression, anxiety, insomnia, and chronic fatigue. Nurses are expected to offer physical and mental support to these patients. Cognitive behavior therapy (CBT) is commonly used in psychiatry as well as in the treatment of patients with breast cancer. CBT is believed to reduce mental distress in patients by changing their negative cognitive schema. The present article discusses the mental problems of patients with breast cancer and introduces the effects of using CBT on patients with breast cancer. Successful examples of training clinical nurses to apply CBT to the patients are introduced in order to facilitate the design of effective CBT training programs for nurses that improve professional knowledge and skills in dealing with the mental health problems of these patients and further enhance the quality of nursing care.

Interleukin-33 increases antibacterial defense by activation of inducible nitric oxide synthase in skin.

Interleukin-33 (IL-33) is associated with multiple diseases, including asthma, rheumatoid arthritis, tissue injuries and infections. Although IL-33 has been indicated to be involved in Staphylococcus aureus (S. aureus) wound infection, little is known about how IL-33 is regulated as a mechanism to increase host defense against skin bacterial infections. To explore the underlying intricate mechanism we first evaluated the expression of IL-33 in skin from S. aureus-infected human patients. Compared to normal controls, IL-33 was abundantly increased in skin of S. aureus-infected patients. We next developed a S. aureus cutaneous infection mouse model and found that IL-33 was significantly increased in dermal macrophages of infected mouse skin. The expression of IL-33 by macrophages was induced by staphylococcal peptidoglycan (PGN) and lipoteichoic acid (LTA) via activation of toll-like receptor 2(TLR2)-mitogen-activated protein kinase (MAPK)-AKT-signal transducer and activator of transcription 3(STAT3) signaling pathway as PGN and LTA failed to induce IL-33 in Tlr2-deficient peritoneal macrophages, and MAPK,AKT, STAT3 inhibitors significantly decreased PGN- or LTA-induced IL-33. IL-33, in turn, acted on macrophages to induce microbicidal nitric oxygen (NO) release. This induction was dependent on inducible nitric oxide synthase (iNOS) activation, as treatment of macrophages with an inhibitor of iNOS, aminoguanidine, significantly decreased IL-33-induced NO release. Moreover, aminoguanidine significantly blocked the capacity of IL-33 to inhibit the growth of S. aureus, and IL-33 silencing in macrophages significantly increased the survival of S. aureus in macrophages. Furthermore, the administration of IL-33-neutralizing antibody into mouse skin decreased iNOS production but increased the survival of S. aureus in skin. These findings reveal that IL-33 can promote antimicrobial capacity of dermal macrophages, thus enhancing antimicrobial defense against skin bacterial infections.

Oral antibiotic treatment induces skin microbiota dysbiosis and influences wound healing.

Antibiotic treatment eliminates commensal bacteria and impairs mucosal innate immune defenses in the gut. However, whether oral antibiotic treatment could alter the composition of the microbiota on the skin surface and influence innate immune responses remains unclear. To test this, mice were treated with vancomycin for 7 days and then wounds were made on the back skin of the mice. Five days later, scar tissue from each mouse was collected for bacterial enumeration, the bacterial composition on the scar and unwounded skin was determined using 16S RNA gene-based pyrosequencing analysis, and skin around wounds was collected for RNA extraction. Compared with the control group, the overall density and composition of skin bacteria were altered, and the proportion of Staphylococcus-related sequences was reduced in the vancomycin-treated group. Moreover, vancomycin treatment decreased the expression of RegIIIγ and interleukin (IL)-17 in the wounded skin. Taken together, our data demonstrate that antibiotic treatment decreases the bacterial density and alters the bacterial composition in skin wounds, followed by a decrease in RegIIIγ expression, which may contribute to the delayed wound repair. Our findings also indicate that antibiotic therapy should be carefully considered in the treatment of skin injury.

Skin mast cells protect mice against vaccinia virus by triggering mast cell receptor S1PR2 and releasing antimicrobial peptides.

Mast cells (MCs) are well-known effectors of allergic reactions and are considered sentinels in the skin and mucosa. In addition, through their production of cathelicidin, MCs have the capacity to oppose invading pathogens. We therefore hypothesized that MCs could act as sentinels in the skin against viral infections using antimicrobial peptides. In this study, we demonstrate that MCs react to vaccinia virus (VV) and degranulate using a membrane-activated pathway that leads to antimicrobial peptide discharge and virus inactivation. This finding was supported using a mouse model of viral infection. MC-deficient (Kit(wsh-/-)) mice were more susceptible to skin VV infection than the wild type animals, whereas Kit(wsh-/-) mice reconstituted with MCs in the skin showed a normal response to VV. Using MCs derived from mice deficient in cathelicidin antimicrobial peptide, we showed that antimicrobial peptides are one important antiviral granule component in in vivo skin infections. In conclusion, we demonstrate that MC presence protects mice from VV skin infection, MC degranulation is required for protecting mice from VV, neutralizing Ab to the L1 fusion entry protein of VV inhibits degranulation apparently by preventing S1PR2 activation by viral membrane lipids, and antimicrobial peptide release from MC granules is necessary to inactivate VV infectivity.

IL-17 family cytokines in inflammatory or autoimmune skin diseases.

As potent pro-inflammatory mediators, IL-17 family cytokines play crucial roles in the pathogenesis of various inflammatory and autoimmune skin disorders. Although substantial progress has been achieved in understanding the pivotal role of IL-17A signaling in psoriasis, leading to the development of highly effective biologics, the functions of other IL-17 family members in inflammatory or autoimmune skin diseases remain less explored. In this review, we provide a comprehensive overview of IL-17 family cytokines and their receptors, with a particular focus on the recent advancements in identifying cellular sources, receptors and signaling pathways regulated by these cytokines. At the end, we discuss how the aberrant functions of IL-17 family cytokines contribute to the pathogenesis of diverse inflammatory or autoimmune skin diseases.

Rapid analysis of Bacillus cereus spore biomarkers based on porous channel cuttlebone SERS substrate.

BACKGROUND: Bacillus cereus (B. cereus) is a widespread conditional pathogen that affects food safety and human health. Conventional methods such as bacteria culture and polymerase chain reaction (PCR) are difficult to use for rapid identification of bacterial spores because of the relatively long analysis times. From a human health perspective, there is an urgent need to develop an ultrasensitive, rapid, and accurate method for the detection of B. cereus spores. RESULTS: The study proposed a new method for rapidly and sensitively detecting the biomarkers of bacterial spores via surface-enhanced Raman spectroscopy (SERS) combined with electrochemical enrichment. The 2,6-Pyridinedicarboxylic acid (DPA) was used as the model analyte to acts as a biomarker of B. cereus spores. The SERS substrate was developed via the in-situ generation of Ag nanoparticles (AgNPs) in a cuttlebone-derived organic matrix (CDOM). Because of the depletion of chitin reduction sites on the CDOM, the pores of the porous channels expanded. The pores diameter of the AgNPs/CDOM porous channel was found to be in the range of 0.7-1.3 nm through molecular diffusion experiments. Based on the porosity of AgNPs/CDOM substrates and the high sensitivity of SERS substrates, the sensor can rapidly and accurately electronically enrich DPA in 40 s with the limit of detection (LOD) of 0.3 nM. SIGNIFICANCE: The results demonstrate that electrochemically assisted SERS substrates can be served as a high sensitivity electrochemical-enrichment device for the rapid and sensitive detection of bacterial spores with minimal interference from potentially coexisting species in biological samples. In this study, it opens up a platform to explore the application of porous channels in natural bio-derived materials in the field of food safety.

DDX5 inhibits hyaline cartilage fibrosis and degradation in osteoarthritis via alternative splicing and G-quadruplex unwinding.

Hyaline cartilage fibrosis is typically considered an end-stage pathology of osteoarthritis (OA), which results in changes to the extracellular matrix. However, the mechanism behind this is largely unclear. Here, we found that the RNA helicase DDX5 was dramatically downregulated during the progression of OA. DDX5 deficiency increased fibrosis phenotype by upregulating COL1 expression and downregulating COL2 expression. In addition, loss of DDX5 aggravated cartilage degradation by inducing the production of cartilage-degrading enzymes. Chondrocyte-specific deletion of Ddx5 led to more severe cartilage lesions in the mouse OA model. Mechanistically, weakened DDX5 resulted in abundance of the Fn1-AS-WT and Plod2-AS-WT transcripts, which promoted expression of fibrosis-related genes (Col1, Acta2) and extracellular matrix degradation genes (Mmp13, Nos2 and so on), respectively. Additionally, loss of DDX5 prevented the unfolding Col2 promoter G-quadruplex, thereby reducing COL2 production. Together, our data suggest that strategies aimed at the upregulation of DDX5 hold significant potential for the treatment of cartilage fibrosis and degradation in OA.

N6-methyladenosine modification-tuned lipid metabolism controls skin immune homeostasis via regulating neutrophil chemotaxis.

Disrupted N6-methyladenosine (m6A) modification modulates various inflammatory disorders. However, the role of m6A in regulating cutaneous inflammation remains elusive. Here, we reveal that the m6A and its methyltransferase METTL3 are down-regulated in keratinocytes in inflammatory skin diseases. Inducible deletion of Mettl3 in murine keratinocytes results in spontaneous skin inflammation and increases susceptibility to cutaneous inflammation with activation of neutrophil recruitment. Therapeutically, restoration of m6A alleviates the disease phenotypes in mice and suppresses inflammation in human biopsy specimens. We support a model in which m6A modification stabilizes the mRNA of the lipid-metabolizing enzyme ELOVL6 via the m6A reader IGF2BP3, leading to a rewiring of fatty acid metabolism with a reduction in palmitic acid accumulation and, consequently, suppressing neutrophil chemotaxis in cutaneous inflammation. Our findings highlight a previously unrecognized epithelial-intrinsic m6A modification-lipid metabolism pathway that is essential for maintaining epidermal and immune homeostasis and lay the basis for potential therapeutic targeting of m6A modulators to attenuate inflammatory skin diseases.

Etanercept decreases the innate immune wounding response in psoriasis.

Cathelicidin is increased when normal skin is injured and in psoriasis lesions where it has been suggested to play a pivotal role in inflammation through interactions with self-DNA and toll-like receptor 9 (TLR-9) in keratinocytes and plasmacytoid dendritic cells. Because of etanercept's success in treating psoriasis, we hypothesized that etanercept may suppress TLR-9 and cathelicidin induction. Examination of experimentally induced wounds of psoriatic lesional and non-lesional skin, and comparison with wounded normal skin, shows that the induction of cathelicidin and TLR-9 is greatly enhanced in lesional psoriatic skin. Six weeks of etanercept appears not to affect the baseline expression of cathelicidin or TLR-9, but does blunt the induction of cathelicidin in psoriasis with wounding. These findings support the role of cathelicidin in the enhancement of local inflammation in psoriasis and may partially explain one of the mechanisms enabling TNF-α inhibitors to successfully treat this disorder.

Multiview Spectral Clustering Based on Consensus Neighbor Strategy.

Multiview spectral clustering, renowned for its spatial learning capability, has garnered significant attention in the data mining field. However, existing methods assume that the optimal consensus adjacency matrix is confined within the space spanned by each view's adjacency matrix. This constraint restricts the feasible domain of the algorithm and hinders the exploration of the optimal consensus adjacency matrix. To address this limitation, we propose a novel and convex strategy, termed the consensus neighbor strategy, for learning the optimal consensus adjacency matrix. This approach constructs the optimal consensus adjacency matrix by capturing the consensus local structure of each sample across all views, thereby expanding the search space and facilitating the discovery of the optimal consensus adjacency matrix. Furthermore, we introduce the concept of a correlation measuring matrix to prevent trivial solution. We develop an efficient iterative algorithm to solve the resulting optimization problem, benefitting from the convex nature of our model, which ensures convergence to a global optimum. Experimental results on 16 multiview datasets demonstrate that our proposed algorithm surpasses state-of-the-art methods in terms of its robust consensus representation learning capability. The code of this article is uploaded to https://github.com/PhdJiayiTang/Consensus-Neighbor-Strategy.git.