S. epidermidis Rescues Allergic Contact Dermatitis in Sphingosine 1-Phosphate Receptor 2-Deficient Skin.

Recent studies have identified a subtype of the S1P-receptor family called sphingosine-1-phosphate receptor 2 (S1PR2), which plays a crucial role in maintaining the skin barrier. It has been observed that S1PR2 and Staphylococcus epidermidis (S. epidermidis) work together to regulate the skin barrier. However, the interaction between these two factors is still unclear. To investigate this, a study was conducted on healthy skin and allergic contact dermatitis (ACD) using 3,4-Dibutoxy-3-cyclobutene-1,2-dione (SADBE) on the ears of S1pr2fl/fl and S1pr2fl/flK14-Cre mice and using 1 × 106 CFU of S. epidermidis to examine its effects on the skin. The results showed that in S. epidermidis-conditioned ACD, the ear thickness of S1pr2fl/flK14-Cre mice was lower than that of S1pr2fl/fl mice, and mRNA expressions of Il-1ß and Cxcl2 of S1pr2fl/flK14-Cre mice were lower than that of S1pr2fl/fl mice in ACD with S. epidermidis. Furthermore, the gene expression of Claudin-1 and Occludin in S1pr2fl/flK14-Cre mice was higher than that of S1pr2fl/fl mice in ACD with S. epidermidis. The study concludes that S. epidermidis colonization improves the skin barrier and prevents ACD even when S1P signaling malfunctions.

Factors Influencing Marker Expressions of Cultured Human Cord Blood-Derived Mast Cells.

Mast cells (MCs) are tissue-resident immune cells of a hematopoietic origin that play vital roles in innate and adaptive immunity. Human MCs can be isolated and differentiated from various tissue sources, including cord blood, when supplemented with cytokines such as stem cell factor, interleukin 3, and interleukin 6. Our current research study has shown significant differences in the marker expressions of human cord blood-derived mast cells (hCBMCs) based on donor dependency and the type of medium used for culturing and differentiation. These findings are particularly relevant given the challenges of obtaining specialty media influencing MC phenotypic marker expressions. We found that hCBMCs cultured in StemSpanTM-XF medium had a moderate expression of mast/stem cell growth factor receptor Kit (c-KIT) (mRNA and protein), low expressions of FcεRI (mRNA) and TLR2 (mRNA and protein) but had high levels of MRGPRX2 (mRNA and protein) expressions. In contrast, hCBMCs cultured in Stem Line II medium expressed FcεRI and TLR2 (mRNA and protein) with higher c-KIT but had lower MRGPRX2 expressions compared to the hCBMCs cultured in the StemSpanTM-XF medium. These results suggest that it is crucial to consider both donor dependency and the medium when investigating MC functions and that further research is needed to fully understand the impact of these factors on the hCBMC marker expressions.

The microbiome of the "sterile" pustules in palmoplantar pustulosis.

The skin microbiome influences skin pathophysiology. Palmoplantar pustulosis (PPP) is a chronic skin disease characterized by infectious-like pustules on the palms and soles. These pustules are thought to be sterile because bacterial cultures obtained from the pustules are negative. However, culture methods are limited in their ability to identify all bacteria on the skin. We hypothesized that the "sterile" pustules of PPP do not lack bacteria, but rather contain a microbiome. To test this hypothesis, we identified bacteria in "sterile" pustules using non-culture methods. We conducted Sanger and 16S rRNA sequencing using primers specific to the V1-V2 region in PPP-pustulovesicles (PVs) (n = 43) and pompholyx vesicle fluids (n = 15). Sanger sequencing identified some Staphylococcus, Propionibacterium, Streptococcus and Pyrinomonas species in PPP-PVs but failed to identify any bacteria in most of the pompholyx vesicles. 16S rRNA sequencing of PPP-PVs indicated the presence of a microbiome that included various phyla, including Firmicutes, Proteobacteria, Actinobacteria and Bacteroidetes. At the genus level, smokers had higher levels of Staphylococcus in PPP-PVs compared with non-smokers. These results indicate that a microbiome exists in "sterile" pustules of PPP and that PPP smokers had higher levels of Staphylococcus in pustules. It is therefore necessary to reconsider the pathogenesis of PPP from the perspective of the microbiome.

The Role of Sphingolipids and Sphingosine-1-phosphate-Sphingosine-1-phosphate-receptor Signaling in Psoriasis.

Psoriasis is a long-lasting skin condition characterized by redness and thick silver scales on the skin's surface. It involves various skin cells, including keratinocytes, dendritic cells, T lymphocytes, and neutrophils. The treatments for psoriasis range from topical to systemic therapies, but they only alleviate the symptoms and do not provide a fundamental cure. Moreover, systemic treatments have the disadvantage of suppressing the entire body's immune system. Therefore, a new treatment strategy with minimal impact on the immune system is required. Recent studies have shown that sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate (S1P), play a significant role in psoriasis. Specific S1P-S1P-receptor (S1PR) signaling pathways have been identified as crucial to psoriasis inflammation. Based on these findings, S1PR modulators have been investigated and have been found to improve psoriasis inflammation. This review will discuss the metabolic pathways of sphingolipids, the individual functions of these metabolites, and their potential as a new therapeutic approach to psoriasis.

Mast cell tolerance in the skin microenvironment to commensal bacteria is controlled by fibroblasts.

Activation and degranulation of mast cells (MCs) is an essential aspect of innate and adaptive immunity. Skin MCs, the most exposed to the external environment, are at risk of quickly degranulating with potentially severe consequences. Here, we define how MCs assume a tolerant phenotype via crosstalk with dermal fibroblasts (dFBs) and how this phenotype reduces unnecessary inflammation when in contact with beneficial commensal bacteria. We explore the interaction of human MCs (HMCs) and dFBs in the human skin microenvironment and test how this interaction controls MC inflammatory response by inhibiting the nuclear factor κB (NF-κB) pathway. We show that the extracellular matrix hyaluronic acid, as the activator of the regulatory zinc finger (de)ubiquitinating enzyme A20/tumor necrosis factor α-induced protein 3 (TNFAIP3), is responsible for the reduced HMC response to commensal bacteria. The role of hyaluronic acid as an anti-inflammatory ligand on MCs opens new avenues for the potential treatment of inflammatory and allergic disorders.

Sphingosine 1-Phosphate Signaling at the Skin Barrier Interface.

Sphingosine 1-phosphate (S1P) is a product of membrane sphingolipid metabolism. S1P is secreted and acts via G-protein-coupled receptors, S1PR1-5, and is involved in diverse cellular functions, including cell proliferation, immune suppression, and cardiovascular functions. Recent studies have shown that the effects of S1P signaling are extended further by coupling the different S1P receptors and their respective downstream signaling pathways. Our group has recently reported that S1P inhibits cell proliferation and induces differentiation in human keratinocytes. There is a growing understanding of the connection between S1P signaling, skin barrier function, and skin diseases. For example, the activation of S1PR1 and S1PR2 during bacterial invasion regulates the synthesis of inflammatory cytokines in human keratinocytes. Moreover, S1P-S1PR2 signaling is involved in the production of inflammatory cytokines and can be triggered by epidermal mechanical stress and bacterial invasion. This review highlights how S1P affects human keratinocyte proliferation, differentiation, immunoreaction, and mast cell immune response, in addition to its effects on the skin barrier interface. Finally, studies targeting S1P-S1PR signaling involved in inflammatory skin diseases are also presented.

Nail lesions in palmoplantar pustulosis and pustulotic arthro-osteitis impairs patients' quality of life: Suggesting new assessment tool of PPP nail lesions.

BACKGROUND: Palmoplantar pustulosis (PPP) sometimes presents with nail lesions, which affect the patients' quality of life (QOL). However, little is known about nail lesions in PPP, and there is currently no established method for assessing them. OBJECTIVE: This study aimed to analyze the impact of PPP-related nail lesions with the patients' QOL. In addition, we considered whether they might constitute a risk factor of pustulotic arthro-osteitis (PAO).' METHODS: A total of 178 patients with PPP were enrolled. Among the 178 patients, 66 patients participated in the following quality of life questionnaires; GHQ28, DLQI, and Skindex-16. The severity of the nail lesions was classified according to the Nail Psoriasis Severity Index (NAPSI), and the types of nail lesion were investigated. RESULTS: The DLQI, Skindex-16 and PPPASI scores were significantly higher in patients with nail lesions than in those without them. Indentions, transverse ridging, and nail thickening were relatively common in PPP. Nail lesions were unrelated to the presence of PAO complications, but leukonychia and discoloration were likely to be related to PAO lesion site. CONCLUSIONS: The study demonstrated that the presence of nail lesions is associated with a decreased QOL regardless of the severity of the skin lesions. The nail lesions were not a risk factor of PAO, but a predictor of skin lesion severity and PAO lesion site. Given this association, indention, transverse ridging, and thickening of the nail, currently not included in the NAPSI, should be added as an assessment item in the evaluation of PPP nail lesions.

Characteristics of Japanese patients with pustulotic arthro-osteitis associated with palmoplantar pustulosis: a multicenter study.

BACKGROUND: Pustulotic arthro-osteitis (PAO) is a major comorbidity of palmoplantar pustulosis (PPP), which is frequently seen in Japanese patients. To determine the characteristics of Japanese patients with PAO, we conducted a multicenter, retrospective epidemiologic survey at four university hospitals. METHODS: Clinical features including age, gender, duration of disease, extrapalmoplantar lesion, smoking habit, focal infection, site of joint pain, bone scintigraphy with Technetium99 , and therapies were retrospectively evaluated. RESULTS: In total, 165 patients with PAO were identified among 576 patients with PPP (28.6%). The male to female ratio was 1 : 3.7, and the mean age was 50.2 years. The mean disease duration of PAO was 6.0 years. Smoking habit was observed in 104 patients. Focal infection was detected in 74 patients, who developed tonsillar infection (n = 41), sinusitis (8), odontogenic infection (40), and others (2). Fifteen patients had multifocal infection. Technetium bone scintigraphy was performed in 97 cases. Increased uptake was most frequently observed in the sternocostoclavicular regions, followed by wrist and ankle, sacroiliac joint, knee and elbow, finger and toe, lumbar spine, thoracic spine, scapula, and thigh. Patients were mainly treated with nonsteroidal anti-inflammatory drugs, methotrexate, cyclosporine, antibiotics, and biologics, as well as tonsillectomy and dental treatment. CONCLUSION: PAO frequently involves the anterior chest wall of middle-aged women with smoking habit and is closely associated with focal infection.

Diagnostic histopathological features distinguishing palmoplantar pustulosis from pompholyx.

Palmoplantar pustulosis (PPP) and pompholyx are both chronic and relapsing diseases occurring on the palms and soles. Although these two diseases have been considered completely different from each other, it is sometimes very difficult even for dermatologists to differentiate them from each other because of their similarities in clinical presentation. In this study, we aimed to analyze the histopathological features of PPP and pompholyx and find out "clues" to differentiate between PPP and pompholyx by their histopathological features. The histopathology of 11 PPP and six pompholyx patients, who were diagnosed with typical clinical history and histopathology, were carefully observed. PPP cases were divided into three phases (vesicle, pustulovesicule and pustule) and pompholyx cases were divided into two phases (vesicle and pustule), and histopathological findings and a 4-point checklist to distinguish between PPP and pompholyx were preliminarily established. To confirm whether the checklist establishes the clues for diagnosis, biopsy samples from 43 patients (32 PPP and 11 pompholyx) who had been already diagnosed at five hospitals were examined according to our checklist without any additional clinical information. According to our 4-point checklist, 31 of 32 PPP patients and all 11 pompholyx patients were diagnosed histopathologically consistent with their clinical diagnosis. In conclusion, histopathological findings of "vesicles without spongiosis" and "microabscess on the edges of vesicles" would be impact points for the differential diagnosis between PPP and pompholyx. The 4-point checklist was trustworthy to distinguish between PPP and pompholyx.