Dietary supplementation with blueberry partially restores T-cell-mediated function in high-fat-diet-induced obese mice.

Blueberry, rich in antioxidant and anti-inflammatory phytochemicals, has been demonstrated to lower inflammatory status in adipose induced by high-fat diet (HFD) and obesity. The effect of blueberry on systemic immune functions has not been examined. C57BL/6 mice were randomised to one of three diets - low-fat diet (LFD), HFD and HFD plus 4 % (w/w) blueberry (HFD+B) - for 8 or 12 weeks. Ex vivo T-cell mitogens (concanavalin A (Con A); phytohaemagglutinin), T-cell antibody (anti-CD3; anti-CD3/CD28)-stimulated T-cell proliferation and cytokine production were assessed. After 8 weeks, both HFD groups weighed more (>4 g) than the LFD group; after 12 weeks, HFD+B-fed mice weighed more (>6 g) and had 41 % more adipose tissue than HFD-fed mice (P<0·05). After 12 weeks, T-cell proliferation was less in both HFD groups, compared with the LFD group. HFD-associated decrements in T-cell proliferation were partially (10-50 %) prevented by blueberry supplementation. At 12 weeks, splenocytes from HFD mice, but not from HFD+B mice, produced 51 % less IL-4 (CD3/CD28) and 57 % less interferon-γ (Con A) compared with splenocytes from LFD mice (P<0·05). In response to lipopolysaccharide challenge, splenocytes from both HFD groups produced 24-30 % less IL-6 and 27-33 % less TNF-α compared with splenocytes from LFD mice (P<0·05), indicating impaired acute innate immune response. By demonstrating deleterious impacts of HFD feeding on T-cell proliferation and splenocyte immune responses, our results provide insights into how HFD/obesity can disrupt systemic immune function. The protective effects of blueberry suggest that dietary blueberry can buttress T-cell and systemic immune function against HFD-obesity-associated insults.

An update on diet and nutritional factors in systemic lupus erythematosus management.

Systemic lupus erythematosus (SLE) is a chronic inflammatory and autoimmune disease characterised by multiple organ involvement and a large number of complications. SLE management remains complicated owing to the biological heterogeneity between patients and the lack of safe and specific targeted therapies. There is evidence that dietary factors can contribute to the geoepidemiology of autoimmune diseases such as SLE. Thus, diet therapy could be a promising approach in SLE owing to both its potential prophylactic effects, without the side effects of classical pharmacology, and its contribution to reducing co-morbidities and improving quality of life in patients with SLE. However, the question arises as to whether nutrients could ameliorate or exacerbate SLE and how they could modulate inflammation and immune function at a molecular level. The present review summarises preclinical and clinical experiences to provide the reader with an update of the positive and negative aspects of macro- and micronutrients and other nutritional factors, including dietary phenols, on SLE, focusing on the mechanisms of action involved.

Association between obesity and asthma - epidemiology, pathophysiology and clinical profile.

Obesity is a risk factor for asthma, and obese asthmatics have lower disease control and increased symptom severity. Several putative links have been proposed, including genetics, mechanical restriction of the chest and the intake of corticosteroids. The most consistent evidence, however, comes from studies of cytokines produced by the adipose tissue called adipokines. Adipokine imbalance is associated with both proinflammatory status and asthma. Although reverse causation has been proposed, it is now acknowledged that obesity precedes asthma symptoms. Nevertheless, prenatal origins of both conditions complicate the search for causality. There is a confirmed role of neuro-immune cross-talk mediating obesity-induced asthma, with leptin playing a key role in these processes. Obesity-induced asthma is now considered a distinct asthma phenotype. In fact, it is one of the most important determinants of asthma phenotypes. Two main subphenotypes have been distinguished. The first phenotype, which affects adult women, is characterised by later onset and is more likely to be non-atopic. The childhood obesity-induced asthma phenotype is characterised by primary and predominantly atopic asthma. In obesity-induced asthma, the immune responses are shifted towards T helper (Th) 1 polarisation rather than the typical atopic Th2 immunological profile. Moreover, obese asthmatics might respond differently to environmental triggers. The high cost of treatment of obesity-related asthma, and the burden it causes for the patients and their families call for urgent intervention. Phenotype-specific approaches seem to be crucial for the success of prevention and treatment.

Maternal fatty acid desaturase genotype correlates with infant immune responses at 6 months.

Breast milk long-chain PUFA (LCPUFA) have been associated with changes in early life immune responses and may modulate T-cell function in infancy. We studied the effect of maternal fatty acid desaturase (FADS) genotype and breast milk LCPUFA levels on infants' blood T-cell profiles and ex vivo-produced cytokines after anti-CD3/CD28 stimulation of peripheral blood mononuclear cells in 6-month-old infants from the Copenhagen Prospective Study of Asthma in Childhood birth cohort. LCPUFA concentrations of breast milk were assessed at 4 weeks of age, and FADS SNP were determined in both mothers and infants (n 109). In general, breast milk arachidonic acid (AA) levels were inversely correlated with the production of IL-10 (r -0.25; P=0.004), IL-17 (r -0.24; P=0.005), IL-5 (r -0.21; P=0.014) and IL-13 (r -0.17; P=0.047), whereas EPA was positively correlated with the counts of blood regulatory T-cells and cytotoxic T-cells and decreased T-helper cell counts. The minor FADS alleles were associated with lower breast milk AA and EPA, and infants of mothers carrying the minor allele of FADS SNP rs174556 had higher production of IL-10 (r -0.23; P=0.018), IL-17 (r -0.25; P=0.009) and IL-5 (r -0.21; P=0.038) from ex vivo-activated immune cells. We observed no association between T-cell distribution and maternal or infant FADS gene variants. We conclude that increased maternal LCPUFA synthesis and breast milk AA are associated with decreased levels of IL-5, IL-13 (type-2 related), IL-17 (type-17 related) and IL-10 (regulatory immune responses), but not with interferon-γ and TNF-α, which could be due to an effect of the maternal FADS variants on the offspring immune response transferred via breast milk LCPUFA.

Modulation of Inflammatory Proteins in Serum May Reflect Cutaneous Immune Responses in Cancer Immunotherapy.

Diphencyprone (DPCP), a topical contact sensitizer, has shown efficacy in treating cutaneous melanoma metastases, including at times beyond the directly treated sites, but biomarkers indicative of treatment response have not been characterized. Thus, we performed a proteomic analysis of the skin and serum of five patients with cutaneous melanoma metastases treated with DPCP on days 0, 63, and 112 of the treatment course. In the serum, we found a significant upregulation (P < 0.05) in 13 of 96 assessed immuno-oncology proteins after DPCP treatment. Upregulated proteins included those of the T helper 1 axis (CXCL9, CXCL10), immune checkpoint proteins (PD-1), and various proteins with roles in promoting tumor immunity such as CD80 and TNFRSF4/9. Given the positive clinical response to topical treatment noted in the five patients studied, these proteins may represent prognostic biomarkers in the serum for evaluating the efficacy of DPCP treatment of cutaneous melanoma metastases. Because DPCP does not lead to nonspecific immune-related adverse events seen with immune checkpoint inhibitors, our study provides evidence for potential tumor-specific systemic immune activation and systemic antitumor effectors elicited by topical DPCP.

Thymus vulgaris, a natural pharmacy against COVID-19: A molecular review.

Introduction: A worldwide pandemic infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a deadly disease called COVID-19. Interaction of the virus and the Angiotensin converting-enzyme 2 (ACE2) receptor leads to an inflammatory-induced tissue damage. Thymus vulgaris L. (TvL) is a plant with a long history in traditional medicine that has antimicrobial, antiseptic, and antiviral properties. Thymol and Carvacrol are two important biological components in Thyme that have anti-inflammatory, antioxidant, and immunomodulatory properties. This study is a molecular review on the potential effects of TvL and its active compounds on SARS-COV2 infection. Method: This is a narrative review in which using PubMed, Scopus, ISI, Cochrane, ScienceDirect, Google scholar, and Arxiv preprint databases, the molecular mechanisms of therapeutic and protective effects of TvL and its active compounds have been discussed regarding the molecular pathogenesis in COVID-19. Results: Thyme could suppress TNF-alpha, IL-6, and other inflammatory cytokines. It also enhances the anti-inflammatory cytokines like TGF-beta and IL-10. Thyme extract acts also as an inhibitor of cytokines IL-1-beta and IL-8, at both mRNA and protein levels. Thymol may also control the progression of neuro-inflammation toward neurological disease by reducing some factors. Thyme and its active ingredients, especially Thymol and Carvacrol, have also positive effects on the renin-angiotensin system (RAS) and intestinal microbiota. Conclusions: Accordingly, TvL and its bioactive components may prevent COVID-19 complications and has a potential protective role against the deleterious consequences of the disease.

Transcriptomic Profiling of Plaque Psoriasis and Cutaneous T-Cell Subsets during Treatment with Secukinumab.

The IL-17A inhibitor secukinumab is efficacious for the treatment of psoriasis. To better understand its mechanism of action, we investigated its impact on psoriatic lesions from 15 patients with moderate-to-severe plaque psoriasis undergoing secukinumab treatment. We characterized the longitudinal transcriptomic changes of whole lesional skin tissue as well as cutaneous CD4+ and CD8+ T effector cells and CD4+ T regulatory cells across 12 weeks of treatment. Secukinumab was clinically effective and reduced disease-associated overexpression of IL17A , IL17F, IL23A, IL23R, and IFNG in whole tissue as soon as 2 weeks after initiation of treatment. IL17A overexpression in T-cell subsets, primarily CD8+ T cells, was also reduced. Although secukinumab treatment resolved 89‒97% of psoriasis-associated expression differences in bulk tissue and T-cell subsets by week 12 of treatment, we observed expression differences involved in IFN signaling and metallothionein synthesis that remained unresolved at this time point as well as potential treatment-associated expression differences involved in IL-15 signaling. These changes were accompanied by shifts in broader immune cell composition on the basis of deconvolution of RNA-sequencing data. In conclusion, our study reveals several phenotypic and cellular changes within the lesion that underlie clinical improvement from secukinumab.

Identification of Keratinocyte Mitogens: Implications for Hyperproliferation in Psoriasis and Atopic Dermatitis.

Psoriasis and atopic dermatitis are chronic inflammatory skin diseases characterized by keratinocyte (KC) hyperproliferation and epidermal acanthosis (hyperplasia). The milieu of disease-associated cytokines and soluble factors is considered a mitogenic factor; however, pinpointing the exact mitogens in this complex microenvironment is challenging. We employed organotypic human epidermal equivalents, faithfully mimicking native epidermal proliferation and stratification, to evaluate the proliferative effects of a broad panel of (literature-based) potential mitogens. The KC GF molecule, the T-helper 2 cytokines IL-4 and IL-13, and the psoriasis-associated cytokine IL-17A caused acanthosis by hyperplasia through a doubling in the number of proliferating KCs. In contrast, IFN-γ lowered proliferation, whereas IL-6, IL-20, IL-22, and oncostatin M induced acanthosis not by hyperproliferation but by hypertrophy. The T-helper 2‒cytokine‒mediated hyperproliferation was Jak/signal transducer and activator of transcription 3 dependent, whereas IL-17A and KC GF induced MAPK/extracellular signal‒regulated kinase kinase/extracellular signal‒regulated kinase‒dependent proliferation. This discovery that key regulators in atopic dermatitis and psoriasis are direct KC mitogens not only adds evidence to their crucial role in the pathophysiological processes but also highlights an additional therapeutic pillar for the mode of action of targeting biologicals (e.g., dupilumab) or small-molecule drugs (e.g., tofacitinib) by the normalization of KC turnover within the epidermal compartment.

Changes in Serum Interferon Gamma and Interleukin-10 in Relation to Direct-Acting Antiviral Therapy of Chronic Hepatitis C Genotype 4: A Pilot Study.

Introduction: This study analyzes the changing levels of circulating inflammatory cytokines Interferon gamma (IFN-γ) and interleukin (IL)-10 (as the main cytokines of T-helper-1 and T-helper-2 immune responses) in patients with chronic hepatitis C virus (HCV) infection undergoing therapy with direct-acting antivirals (DAAs) and to correlate them with laboratory markers. Methods: This Pilot study included 50 HCV monoinfected patients who received DAAs for 12 or 24 weeks. They were followed up monthly during therapy and 3 months after the end of the treatment. Liver disease was determined by transient elastography, in addition to FIB-4 indices. Analysis of IFN-gamma and IL-10 was carried out using an enzyme-linked immunosorbent assay. Results: All patients carried HCV genotype 4. The Sustained virological response was 100% and 92% in cirrhotics and noncirrhotics, respectively. There was no significant difference between groups in baseline IL-10 or IFN-gamma. In noncirrhotics, IL-10 showed a significant reduction at Week 4 after treatment start. In cirrhotics, IL-10 showed a significant reduction at Week 4 after treatment starts and a significant reduction at Week 12 after the end of the treatment. At Week 12 after the end of the treatment, serum IL-10 levels were significantly lower in cirrhotics. IFN-γ showed nonsignificant changes in noncirrhotics. A significant increase of IFN-γ occurred in cirrhotics from Week 4 after treatment starts to 12 weeks after the end of the treatment. IFN-γ was significantly higher in cirrhotics at Week 12 after the end of the treatment. IFN-γ and IL-10 showed different correlations with laboratory markers. Conclusion: Viral eradication induced by DAAs caused a significant change in IL-10 and IFN-gamma.

Type 2 Inflammation Contributes to Skin Barrier Dysfunction in Atopic Dermatitis.

Skin barrier dysfunction, a defining feature of atopic dermatitis (AD), arises from multiple interacting systems. In AD, skin inflammation is caused by host-environment interactions involving keratinocytes as well as tissue-resident immune cells such as type 2 innate lymphoid cells, basophils, mast cells, and T helper type 2 cells, which produce type 2 cytokines, including IL-4, IL-5, IL-13, and IL-31. Type 2 inflammation broadly impacts the expression of genes relevant for barrier function, such as intracellular structural proteins, extracellular lipids, and junctional proteins, and enhances Staphylococcus aureus skin colonization. Systemic anti‒type 2 inflammation therapies may improve dysfunctional skin barrier in AD.

A randomized double blinded placebo controlled clinical trial for the evaluation of green coffee extract on immune health in healthy adults.

Background: The immune system functions to protect the host from a broad array of infectious diseases. Here, we evaluated the in vitro immunomodulatory effects of green coffee extract (GCE), and conducted a double-blinded, randomized and placebo-controlled trial among apparently healthy individuals. Methods: We determined the levels and functions of inflammatory and immune markers viz., phospho-NF-κB p65 ser536, chemotaxis, phagocytosis, TH1/TH2 cytokines and IgG production. We also evaluated several immunological markers such as total leukocyte counts, differential leukocyte counts, NK cell activity, CD4/CD8 ratio, serum immunoglobulin, C-reactive protein (CRP) and pro-inflammatory cytokines (IL-6 and TNF-α). Results and conclusion: GCE significantly inhibited LPS-induced NF-κB p65 ser536 phosphorylation, MCP-1-induced chemotaxis and significantly enhanced phagocytosis and IgG production. In addition, GCE modulated PMA/PHA-induced TH1/TH2 cytokine production. Clinical investigations suggested that the expression of CD56 and CD16 was markedly augmented on NK cells following GCE treatment. GCE significantly enhanced IgA production before and after influenza vaccination. Similarly, IL-6, TNF-α and CRP levels were significantly inhibited by GCE. Together, GCE confers several salubrious immunomodulatory effects at different levels attributing to optimal functioning of immune responses in the host. Taxonomy: Cell biology, Clinical study, Clinical Trial.

Emerging Roles of Adipose Tissue in the Pathogenesis of Psoriasis and Atopic Dermatitis in Obesity.

Obesity is a growing epidemic worldwide, and it is also considered a major environmental factor contributing to the pathogenesis of inflammatory skin diseases, including psoriasis (PSO) and atopic dermatitis (AD). Moreover, obesity worsens the course and impairs the treatment response of these inflammatory skin diseases. Emerging evidence highlights that hypertrophied adipocytes and infiltrated immune cells secrete a variety of molecules, including fatty acids and adipokines, such as leptin, adiponectin, and a panel of cytokines/chemokines that modulate our immune system. In this review, we describe how adipose hypertrophy leads to a chronic low-grade inflammatory state in obesity and how obesity-related inflammatory factors are involved in the pathogenesis of PSO and/or AD. Finally, we discuss the potential role of antimicrobial peptides, mechanical stress and impairment of epidermal barrier function mediated by fast expansion, and dermal fat in modulating skin inflammation. Together, this review summarizes the current literature on how obesity is associated with the pathogenesis of PSO and AD, highlighting the potentially important but overlooked immunomodulatory role of adipose tissue in the skin.

Trichinella-induced immunomodulation: Another tale of helminth success.

Trichinella spiralis is a unique parasite in that both the adults and larvae survive in two different intracellular niches in the same host. The immune response, albeit intense, is highly modulated to ensure the survival of both the host and the parasite. It is skewed to T helper 2 and regulatory arms. Diverse cells from both the innate and adaptive compartments of immunity, including dendritic cells, T regulatory cells, and alternatively activated macrophages are thought to mediate such immunomodulation. The parasite has also an outstanding ability to evade the immune system by several elaborate processes. The molecules derived from the parasites including Trichinella, particularly the components of the excretory-secretory products, are being continually identified and explored for the potential of ameliorating the immunopathology in animal models of diverse inflammatory and autoimmune human diseases. Herein we discuss the various aspects of Trichinella-induced immunomodulation with a special reference to the practical implications of the immune system manipulation in alleviating or possibly curing human diseases.

The Relapse of Psoriasis: Mechanisms and Mysteries.

Over the past decades, tremendous success in the treatment of psoriasis has been achieved using biologics, such as neutralizing antibodies against TNF/TNFR, IL-23, and IL-17A/IL-17RA. Although psoriatic skin lesions appear to resolve after treatment with these biologics, lesions often recur after therapy is discontinued or during therapy. Memory T cells residing in the skin have been considered as the major driver of psoriasis relapse. However, whether structural cells in the skin such as keratinocytes and fibroblasts are involved in the relapse of psoriasis is unknown. In this review, we outline the therapeutic rationale of biologics used in the treatment of psoriasis, summarize different clinical features of psoriasis relapse on the basis of preclinical and clinical data, and specifically discuss how memory T cells and structural cells in the skin are involved in psoriasis relapse. Finally, we discuss the future challenges in the basic or clinical research on psoriasis.

Effect of naturally derived surgical hemostatic materials on the proliferation of A549 human lung adenocarcinoma cells.

Hemostatic materials are generally applied in surgical operations for cancer, but their effects on the growth and recurrence of tumors are unclear. Herein, three commonly used naturally derived hemostatic materials, gelatin sponge, Surgicel (oxidized regenerated cellulose), and biopaper (mixture of sodium hyaluronate and carboxymethyl chitosan), were cocultured with A549 human lung adenocarcinoma cells in vitro. Furthermore, the performance of hemostatic materials and the tumorigenicity of the materials with A549 â€‹cells were observed after subcutaneous implantation into BALB/c mice. The in vitro results showed that biopaper was dissolved quickly, with the highest cell numbers at 2 and 4 days of culture. Gelatin sponges retained their structure and elicited the least cell infiltration during the 2- to 10-day culture. Surgicel partially dissolved and supported cell growth over time. The in vivo results showed that biopaper degraded rapidly and elicited an acute Th1 lymphocyte reaction at 3 days after implantation, which was decreased at 7 days after implantation. The gelatin sponge resisted degradation and evoked a hybrid M1/M2 macrophage reaction at 7-21 days after implantation, and a protumor M2d subset was confirmed. Surgicel resisted early degradation and caused obvious antitumor M2a macrophage reactions. Mice subjected to subcutaneous implantation of A549 â€‹cells and hemostatic materials in the gelatin sponge group had the largest tumor volumes and the shortest overall survival (OS), while the Surgicel and the biopaper group had the smallest volumes and the longest OS. Therefore, although gelatin sponges exhibited cytotoxicity to A549 â€‹cells in vitro, they promoted the growth of A549 â€‹cells in vivo, which was related to chronic M2d macrophage reaction. Surgicel and biopaper inhibited A549 â€‹cell growth in vivo, which is associated with chronic M2a macrophage reaction or acute Th1 lymphocyte reaction.

Regenerative medicine strategies for hair growth and regeneration: A narrative review of literature.

Hair loss, or alopecia, is associated with several psychosocial and medical comorbidities, and it remains an economic burden to individuals and the society. Alopecia is attributable to varied mechanisms and features a multifactorial predisposition, and the available conventional medical interventions have several limitations. Thus, several therapeutic strategies for alopecia in regenerative medicine are currently being explored, with increasing evidence suggesting that mesenchymal stem cell (MSC) implantation, MSC-derived secretome treatment, and blood-derived platelet-rich plasma therapies are potential treatment options. In this review, we searched the Cochrane Library, MEDLINE (PubMed), EMBASE, and Scopus using various combinations of terms, such as "stem cell," "alopecia," "hair loss," "Androgenetic alopecia," "male-pattern hair loss," "female-pattern hair loss," "regenerative hair growth," "cell therapy," "mesenchymal stem cells," "MSC-derived extracellular vesicles," "MSC-derived exosomes," and "platelet-rich plasma" and summarized the most promising regenerative treatments for alopecia. Moreover, further opportunities of improving efficacy and innovative strategies for promoting clinical application were discussed.

Dupilumab Effects on Innate Lymphoid Cell and Helper T Cell Populations in Patients with Atopic Dermatitis.

Group 2 innate lymphoid cells (ILCs) are thought to contribute to the pathogenesis of atopic dermatitis (AD). IL-4 stimulates T helper type 2 (Th2) cells and ILC2s to proliferate and produce cytokines. Dupilumab, an antibody against the IL-4 receptor, is used in AD therapy. We speculated that its efficacy might involve blocking the activation of Th2 cells and ILC2s via IL-4. Here, we examined circulating Th2 cells and ILC2s in 27 Japanese patients with AD before and after the administration of dupilumab. Between 0 and 4 months after dupilumab administration, the percentages of Th2 cells and ILC2s were decreased. Notably, ILC2/3 ratio was decreased after dupilumab treatment. Interestingly, ILC2/3 ratio before dupilumab treatment were significantly higher in high responders than in low responders to dupilumab. To resolve the molecular signatures of the Th2 and ILC2s in AD, we sorted CD4+ T cells and ILCs from peripheral blood and analyzed their transcriptomes using the BD Rhapsody Single-cell RNA sequencing system. Between 0 and 4 months after dupilumab administration, the Th2 and ILC2 cluster gene signatures were downregulated. Thus, dupilumab might improve dermatitis by suppressing the Th2 cell and ILC2 populations and altering the Th2 and ILC2 repertoire in patients with AD.

SB206, a Nitric Oxide-Releasing Topical Medication, Induces the Beginning of the End Sign and Molluscum Clearance.

The beginning of the end (BOTE) sign has been proposed to describe well-recognized clinical signs of inflammation (including erythema, induration, and scale) that predict imminent resolution of molluscum contagiosum (MC). This phenomenon has never been prospectively studied. An integrated analysis of two prospective, 12-week, randomized, double-blind clinical trials of topical nitric oxide-releasing SB206 gel evaluated an association between BOTE sign and MC lesion reduction. Of 707 randomized patients, ~80% exhibited BOTE signs regardless of treatment assignment. At week 12, MC lesion counts decreased from baseline by 50.7% for baseline BOTE+ versus 29.1% for BOTE- (P = 0.0015) vehicle-treated patients compared with a 63.3% decrease for baseline BOTE+ versus 51.7% for BOTE- (P = 0.0194) SB206-treated patients. Among vehicle-treated patients, 48 (22.3%) who were never BOTE+ had an 18.5% reduction from baseline in MC lesion counts versus a 34.0% reduction in 165 patients (76.7%) who experienced BOTE at any time, suggesting that the projected duration of lesion clearance for patients with 18-20 MC lesions is 15 months for BOTE- versus 6 months for BOTE+ patients. Patients who were both BOTE+ and treated with SB206 had the greatest reduction in MC lesion count. SB206 may trigger BOTE signs and shorten the duration of MC infection. The two studies whose data are analyzed in this study are registered at ClinicalTrials.gov with the identifiers NCT03927703 and NCT03927716.

Bath Psoralen Plus UVA Therapy Suppresses Keratinocyte-Derived Chemokines in Pathogenetically Relevant Cells.

Psoriasis is a chronic inflammatory proliferative skin disease involving various types of chemokines regulating immune cell migration, localization, and activation. Bath psoralen plus UVA (PUVA) treatment is an established phototherapy for psoriasis, but its effects on chemokine levels remain unknown. We investigated the levels of 22 serum chemokines in 20 patients with psoriasis first treated with bath PUVA therapy between 2007 and 2011 in a single center and analyzed the associations between the chemokines and disease severity (PASI) before and after therapy to investigate the mechanisms of action of bath PUVA therapy. Before bath PUVA therapy, the PASI scores correlated with the serum levels of CCL17 (r = 0.581), CCL18 (r = 0.462), CCL19 (r = 0.477), and CXCL16 (r = 0.524). After bath PUVA, the serum levels of CCL17, CCL22, CXCL1, and CXCL9 were significantly decreased. Heatmap clustering and network analysis based on statistically significant Spearman correlations among the chemokines showed distinctive changes in the chemokine signature. Our findings revealed that the levels of several chemokines correlated with the disease state of psoriasis. Furthermore, bath PUVA therapy reduced the secretion of keratinocyte-derived chemokines that induce the migration of immune cells important for psoriasis pathogenesis, partly revealing the mechanism of the therapeutic activity.

Deletion of TNFAIP6 Gene in Human Keratinocytes Demonstrates a Role for TSG-6 to Retain Hyaluronan Inside Epidermis.

TSG-6 is a soluble protein secreted in the extracellular matrix by various cell types in response to inflammatory stimuli. TSG-6 interacts with extracellular matrix molecules, particularly hyaluronan (HA), and promotes cutaneous wound closure in mice. Between epidermal cells, the discrete extracellular matrix contains HA and a tiny amount of TSG-6. However, challenges imposed to keratinocytes in reconstructed human epidermis revealed strong induction of TSG-6 expression, after exposure to T helper type 2 cytokines to recapitulate the atopic dermatitis phenotype or after fungal infection that causes secretion of cytokines and antimicrobial peptides. After both types of challenge, enhanced release of TSG-6 happens simultaneously with increased HA production. TSG-6 deficiency in N/TERT keratinocytes was created by inactivating TNFAIP6 using CRISPR/Cas9. Some TSG-6 -/- keratinocytes analyzed through scratch assays tend to migrate more slowly but produce reconstructed human epidermis that exhibits normal morphology and differentiation. Few significant alterations were noticed by transcriptomic analysis. Nevertheless, reduced HA content in TSG-6 -/- reconstructed human epidermis was observed, along with enhanced HA release into the culture medium, and this phenotype was even more pronounced after the challenging conditions. Reintroduction of cells producing TSG-6 in reconstructed human epidermis reduced HA leakage. Our results show a role for TSG-6 in sequestering HA between epidermal cells in response to inflammation.