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BackgroundPsoriasis is an inflammatory skin condition where immune cells play a significant role. The importance of the cross-talk between keratinocytes and immune cells in the pathogenesis of psoriasis has recently been reaffirmed. Recent studies have found that several S1PR functional antagonists, other than S1PR2, are effective in improving psoriasis. This study aims to investigate the role of S1PR2 in psoriasis, that has not been investigated before.MethodsSpatial transcriptomics, RT-qPCR, and flow cytometry were used to map the immune cell landscape and its association with metabolic pathways in an imiquimod (IMQ)-induced psoriasis-like inflammation in S1pr2fl/fl K14-Cre mice that could not sense sphingosine-1-phosphate (S1P) in the epidermis through the S1PR2 receptor.ResultsOur analysis suggests that S1PR2 in keratinocytes plays a major role in psoriasis-like inflammation compared to other S1PRs. It acts as a down-regulator, inhibiting the recruitment of Th17 cells into the skin. In IMQ-induced psoriasis skin, both S1pr2-/- and S1pr2fl/fl K14-Cre mice showed higher expressions of proinflammatory cytokines such as TNF-α, IL-17A, and IL-1β together with higher expressions of MyD88/NF-κB pathway compared to the wild-type mice. Remarkably, in IMQ-treated mice, the deletion of S1pr2 in keratinocytes only resulted in a larger population of Th17 cells in skin-draining lymph nodes. Other S1PR modulators did not improve the worsening of psoriasis-like inflammation caused by S1PR2 deficiency in keratinocytes.ConclusionThis study reaches two main conclusions: signals from keratinocytes play a central role in creating an immune environment that promotes the development of psoriasis, and stimulating S1PR2, instead of suppressing it, represents a potential therapeutic approach for psoriasis.

Summary: 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.

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.

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.

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-1β 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.

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.